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Tweaking the Complex Fibrogenic Role of Lymphocytes in Idiopathic Pulmonary Fibrosis

Article information

Tuberc Respir Dis. 2026;89(2):154-165
Publication date (electronic) : 2025 December 12
doi : https://doi.org/10.4046/trd.2025.0160
Aritra Bhattacharyya,1orcid_icon, Julie D. Saba2
1Human Genetics Unit, Biological Science Division, Indian Statistical Institute, Kolkata, India
2Department of pediatrics, University of California, San Francisco, San Francisco, CA, USA
Address for correspondence Aritra Bhattacharyya Human Genetics Unit, Biological Science Division, Indian Statistical Institute, Kolkata 700108, India E-mail Aribhatt@isical.ac.in
Received 2025 September 29; Revised 2025 November 1; Accepted 2025 December 12.

Abstract

Idiopathic pulmonary fibrosis is a deadly lung disease primarily affecting aged individuals. Even though there are two U.S. Food and Drug Administration-approved drugs, nintedanib and pirfenidone, with a recent addition of another drug, nerandomilast, yet they only reduce the progress of the disease. The mean survival rate is between 5 and 7 years even after treatment with antifibrotics. Cells of lymphoid lineage have been long reported to modulate the outcome of pulmonary fibrosis. In this review, we discuss how the cell of lymphoid lineage regulates the inflammatory niche within the lungs, leading to the development and progress of pulmonary fibrosis. The review also addresses possible therapeutic strategies that can be leveraged by specifically targeting the lymphoid cells in the pulmonary fibrotic niche.

Keywords: Idiopathic Pulmonary Fibrosis; B Lymphocytes; T Lymphocytes; Natural Killer Cells; Natural Killer T Cells; Inflammation

Key Figure

Introduction

Interstitial lung disease (ILD) comprises a wide spectrum of lung diseases due to diverse causes and is associated with pulmonary inflammation. Idiopathic pulmonary fibrosis (IPF) is one of the most common forms of ILD with the exact cause of the disease being unknown [1,2]. Other clinical forms of ILDs include sarcoidosis, hypersensitivity pneumonitis and connective tissue disease-ILD [3]. The incidence rate of IPF varies in different countries as outlined in Table 1 [4-7].

Incidence rate of idiopathic pulmonary fibrosis in different parts of the world

In India, IPF comprises 17% of ILDs and the estimated national prevalence rate is between 51,000 and 102,000 [8]. IPF is associated with high mortality and mostly affects aged individuals. This is likely due to repeated epithelial injury which often leads to cellular senescence in epithelial cells [9] and the induction of senescence associated secretory phenotype, with the cellular release of a pool of inflammatory mediators which promotes pulmonary fibrosis [10]. IPF is characterized by excess deposition of extracellular matrix (ECM) by myofibroblast and in turn loss of lung function such as forced vital capacity [11]. Another aspect of the disease is typical diagnostic delay of 2.1 years [12]. Activation of fibroblast to myofibroblast is aggravated by cells of myeloid and lymphoid lineage, recruited to the site of lung injury. This fibroblast to myofibroblast transition (FMT) is instigated by a host of inflammatory mediators secreted by the immune cells, including transforming growth factor-β (TGF-β) [13]. In our previous review we focused on myeloid lineage activating the mesenchyme compartment [14]. In this current review, we focus on how cells of lymphoid lineage respond and contribute to the inflammatory fibrotic niche within the lungs, and in turn regulate pulmonary fibrosis. We also discuss recent therapeutic strategies by targeting these cells for treatment of pulmonary fibrosis. The different cell types covered in this review include natural killer (NK) cells, natural killer T (NKT) cells and invariant NKT (iNKT) cells, γδ T cells, regulatory T (Treg) cells, T helper (Th) cells—Th1/Th2/Th17/T follicular helper (Tfh) cells and B cells as summarized in Table 2 and Figure 1.

Summary of secreted factors from lymphoid cells in the fibrotic niche

Fig. 1.

Overview of lymphocyte-mesenchyme interaction in a fibrotic lung. Red and green arrows indicate overall inhibition and promotion of pulmonary fibrosis respectively. Tfh: T follicular helper; Treg: regulatory T; IL: interleukin; Th: T helper; IFN-γ: interferon-γ; TGF-β: transforming growth factor-β; MMP-7: matrix metalloproteinase-7; Auto Ab: autoreactive antibodies; NK: natural killer; NKT: natural killer T.

Lymphocytes in the Development and Progression of Pulmonary Fibrosis

1. NK cells

NK cells are a subset of innate lymphoid cells (ILCs) which link the innate and adaptive immune system. Phenotypically, NK cells have been reported to be either cytotoxic circulatory NK cells or pro-inflammatory tissue resident NK cells [15]. The circulatory NK cells are labeled as CD56dimCD16+ whereas the tissue resident NK cells are labeled asCD56brightCD16–. Increased collagen deposition is seen in mice with depleted NK cells as compared to the control mice after induction of bleomycin induced lung injury [16]. Interestingly, the same study shows accumulation of senescent cells in the injured lungs of mice, depleted with NK cells. The possible proposed mechanism is that in the lung microenvironment, especially the fibroblast promotes dysfunctional NK activity, by inducing senescence in NK cells, which in turn impedes the resolution of pulmonary fibrosis [16]. Supporting this NK cell-fibroblast interaction, another group has shown that NK cells remain in proximity with the mesenchyme progenitor cells (MPCs). The same study shows that these MPCs have higher expression of programmed cell death ligand 1 (PD-L1) in fibrotic lungs and disruption of the programmed cell death 1 (PD-1)/PD-L1 pathways enhances NK cell mediated killing of MPCs with better outcome of pulmonary fibrosis [17]. Clinically, it has been shown that the number of NK cells in the lower lobe of IPF lungs is significantly less than that of healthy controls (HC). More specifically, the number of circulatory NK cells is lower in the IPF lower lobe with respect to HC, whereas there is an increase in circulatory NK cells in the blood of the IPF patients, compared to HC [18]. NK cell numbers in broncho-alveolar lavage fluid (BALF) are highest in IPF patients among all the ILDs and in turn determine the survival rate in these IPF patients [19]. PXN, an immune infiltration gene (IIG) is found to be highly expressed in IPF patients compared to HC [20]. On a related note, activated NK cells in IPF have been shown to overexpress PXN [21]. Targeting NK cells therapeutically has produced different results in human versus mouse cells. One such study has shown that interleukin 12 (IL-12) stimulated human NK cells leads to inhibition of type I collagen and α smooth muscle actin (αSMA) in lung fibroblasts. However, caution should be used in interpreting results from murine experiments in understanding the role of NK cells in pulmonary fibrosis. IL-12 stimulated mouse NK cells only reduced type I collagen genes but not αSMA in lung fibroblasts. The proposed mechanism is via the interferon-γ (IFN-γ) secreted from the IL-12 stimulated NK cells [22].

2. NKT cells and iNKT cells

NKT cells are a specialized type of immune cells that recognize lipid antigens. NKT cells are of two types-type I NKT which express invariant T cell receptor α (TCRα) chain, recognizes glycolipid α-galactosyl ceramide (α-Galcer) and are referred to as iNKTs. Type II NKTs recognize lipid antigen and expresses diverse TCR chains [23]. These glycolipid antigens are presented by the antigen presenting cells (APCs) via the antigen presenting molecule CD1d. NKT-deficient mice generated by knocking out CD1d have elevated pulmonary fibrosis in comparison to wild type controls in response to bleomycin induced lung injury. These NKT-deficient mice also have reduced IFN-γ, which strongly suggests that NKT cells reduce pulmonary fibrosis by the production of IFN-γ [24]. Lung fibrosis is often associated with the accumulation of senescent cells. The induction of senescence is not only observed in the mesenchyme compartment, i.e., the fibroblast but also in epithelial and endothelial cells [10]. The mechanism of action that has been proposed is that α-Galcer mediated activation of iNKT cells reduces senescent cell burden thereby leading to a better outcome of pulmonary fibrosis [25]. In sharp contrast to the former study, a study by Calamita et al have shown that in a bleomycin induced lung injury model, treatment of mice with an iNKT inhibitor (GRI-0621) leads to significant reduction of fibrosis by reduction of TGF-β [26]. Clinically, the same group have shown that iNKT cell numbers are higher in the BALF of IPF patients with respect to HC [26]. One possible reason for the contradictory results between the two studies [25,26], is because there are three different cytokine pathways activated by iNKTs, where type 1 secretes IFN-γ, type 2 and type 3 secrete IL-4 and IL-17A respectively [27].

3. γδ T cells

Even though γδ T cells comprise a very small percentage of circulatory T cells, these cells form an important mediator between the innate and adaptive immune systems. In a bleomycin induced lung injury murine model, it has been shown that γδ T cells localize in the fibrotic scar, exhibit an IL-17A secretory phenotype and inhibits Th17 cells via the production of IFN-γ, probably via a feedback loop [28,29]. IL-17A is one of the critical drivers of pulmonary fibrosis [30]. Clinically, it has been shown that γδ T cell number increases in IPF patients compared to HC [31]. In two different studies by Simonian et al. [32] and Pociask et al. [33], have shown that γδ T cells attenuate pulmonary fibrosis by regulating IL-22 and C-X-C motif chemokine 10 (CXCL10) respectively. Recent evidence suggests that γδ T cells target p21+ senescent fibroblasts which express γδ T ligands such as butyrophilin subfamily 3 member A1 (BTN3A1) and further, this γδ T cell-mesenchyme interaction could be a potential target for the treatment of pulmonary fibrosis [34].

4. Treg cells

Treg cells are a subset of CD4+ T cells that maintain immune homeostasis. Tregs constitute around 5% to 10% of CD4+ T cells in human peripheral blood and are identified using CD4+CD25+ along with Forkhead box 3+ (FoxP3+) markers [35-37]. Miyara et al. [38] have shown that there are three subsets of Tregs; activated Tregs (aTregs) which are CD45RA-FoxP3hi, resting Tregs (rTregs) which are CD45RA+FoxP3lo. The aTreg and rTreg form immunosuppressive classes of Treg cells whereas there is a non-immunosuppressive Treg which secretes cytokines and is CD45RA-FoxP3lo [38]. Clinically, even though total Treg numbers in the peripheral blood of IPF patients compared to HC are not different, the composition of Tregs subsets is altered. For example, it was observed that there is a lower percentage of rTregs and a higher percentage of aTregs in IPF subjects compared to HC [39]. Diffusing capacity of the lung for carbon monoxide (DLCO) along with other lung function tests is used to predict the severity of IPF [40]. Interestingly, the percentage of aTregs has been reported to negatively correlate with the DLCO of IPF patients [39]. The role of Tregs during pulmonary fibrosis depends on the phase of the disease. In a murine model of lung injury induced by a single dose of bleomycin, there is an acute inflammatory phase followed by a fibrotic and concluding with a resolution phase. Depletion of Tregs (using anti-CD25 antibody) in the early inflammatory phase, led to a reduction of pulmonary fibrosis. In contrast, depletion of Tregs in the late fibrotic phase led to enhanced pulmonary fibrosis [41]. The proposed mechanism for this dichotomous biphasic response was that Tregs skewed the Th2/Th17 responses. Indeed, Tregs regulate Th17 responses as another study showed that if Tregs are depleted before the bleomycin injury, it often leads to a better outcome of pulmonary phase by modulating the Th17 responses [42]. Thus, Treg cells act as a two-edged sword. They have been reported to secret a host of pro-fibrotic factors such as platelet-derived growth factor (Pdgf) and TGF-β which in turn promotes myofibroblast activation and collagen deposition [43,44]. On the other hand, adoptive transfer of Tregs at d14 post-bleomycin injury led to a reduction of pulmonary fibrosis [45]. Supporting the latter findings, administration of formylindolo[3,2-b]carbazole (FICZ), a ligand for aryl hydrocarbon receptor (AhR) showed an increase in Tregs and a decrease in collagen deposition [46,47]. It is very important to note that the murine model of bleomycin induced pulmonary fibrosis (which is the most widely used model to mimic pulmonary fibrosis), poorly reflects the irreversible development of pulmonary fibrosis in human subjects [48]. Thus, the dual response of Tregs in the murine model may not be the same when Tregs are targeted in IPF patients.

5. Helper T cells

CD4+ Th cells are comprised of various subsets based on the type of cytokines they release. This subsection will address the roles of CD4+ subpopulations including Th1, Th2, Tfh, and Th17 cells in lung fibrosis.

Th1/Th2 cells are subsets of helper T cells which secrete IFN-γ and IL-4, respectively. Th1 cells also secrete IL-2, IL-12, and IL-18. Th2 cells also secrete IL-5, IL-6, and IL-13 [49]. Given their differences in secretory profile, IFN-γ and IL-12 derived from Th1 cells have been shown to have beneficial effects in the prevention of pulmonary fibrosis [50]. A recent study has shown that IFN-γ in combination with one of the standard treatments of IPF, Pirfenidone led to reduction of fibroblast proliferation [51]. Mechanistically, IFN-γ inhibits myofibroblast activation by inhibiting TGF-β signaling pathway. Even though IFN-γ showed a favorable outcome in the murine model of pulmonary fibrosis, the same was not observed in human clinical trials [52]. On the other hand, Th2-derived factors such as IL-4 and IL-13 promote pulmonary fibrosis. Mechanistically, IL-4 and IL-13 promote FMT through the TGF-β signaling pathway [53]. However, IL-13 antibody (tralokinumab) did not show efficacy in clinical trial [54]. The balance of Th1/Th2 responses influence the outcome of pulmonary fibrosis, and these two subpopulations thwart one another’s activities [54]. For example, IL-12 promotes the release of IFN-γ from Th1 cells [50]. This IFN-γ in turn inhibits the release of IL-4 from Th2 cells [55]. As a counter-regulatory mechanism, IL-4 in turn inhibits the secretion of IFN-γ by Th1 cells [56]. Clinically, it was observed that the percentage of Th1 cells increased in the blood of IPF patients [57]. As expected, IFN-γ levels were also higher in the BALF and blood of IPF patients [58]. Th2 cell numbers have been reported to be a crucial marker in the progression of pulmonary fibrosis. A study by Tsukuda et al. [59] have shown an increase in Th2 cell numbers over time in untreated IPF patients.

Tfh cells are a subset of CD4+T cells, located in the germinal centers of secondary lymphoid organs, expressing a wide variety of markers such as transcription factor B-cell lymphoma-6 (BCL6), inducible co-stimulatory molecule (ICOS) and PD-1. Clinically it has been shown that the proportion of Tfh among CD4+ T cells is significantly higher in the peripheral blood of IPF patients with respect to HC [60]. However, the proportion of Tfh in IPF blood did not correlate with lung functions such as DLCO. Among the three U.S. Food and Drug Administration (FDA) approved drugs for IPF, Pirfenidone treatment has shown to correlate with reduced frequency of Tfh cells in the splenic germinal centers in mouse model of chronic graft-versus-host-disease [61]. Mechanistically, the Tfh cell produces IL-21 which is required for B-cell proliferation and is also a key promoter of fibroblast migration [62]. Fibroblast in turn promote Tfh differentiation via the IL-6/IL-6R signaling pathway [63]. On a related note, it has also been shown that IL-21 deficient mice have better outcomes of bleomycin induced pulmonary fibrosis [64]. However, IL-21 is produced by both Tfh and Th17 cells [65], so the role of Tfh derived IL-21 in the development of pulmonary fibrosis may require further analysis.

Th17 cells are another Th cell subpopulation, named because they are a major source of IL-17, an important driver of pulmonary fibrosis [66]. Mechanistically, IL-17 once secreted, binds to its receptor, IL-17R, which is highly expressed on fibroblasts in addition to other cell types [67]. This in turn leads to fibroblast mediated deposition of ECM. siRNA-mediated knockdown of IL-17R on fibroblast led to a decrease in ECM production in the presence of IL-17 [68]. Not only ECM production but IL-17 also promotes TGF-β signaling [66]. There is a feedback mechanism by which TGF-β also promotes Th17 differentiation from naïve T cells has been described [69]. Clinically, in two different studies, it was shown that Th17 cells go down in IPF patients, leading to disbalance in the Th17/Treg ratio in IPF patients [57,70]. Th17/Treg ratio can also predict the acute exacerbation (AE) of IPF patients. AE of IPF patients is a rapid decline in respiratory function and IPF patients who experiences AE have a mean survival rate of 3 to 4 months [71]. Interestingly, Senoo et al. [72] have shown IL-17 and IL-23 are higher in BALF of murine model of pulmonary fibrosis with AE, suggesting a critical role of IL-17 in the role of prognosis of AE in IPF. In one such study, it has been shown a significant upregulation of all Th17 cell factors such as retinoic acid related orphan receptor γt (RORγt), IL-17, signal transducers and activator of transcription 3 (STAT3) in BALF of IPF patients compared to HC [73]. Therapeutically, in vivo studies for inhibition of Th17 differentiation using donepezil, a cholinesterase inhibitor, led to a reduction of fibroblast activation and in turn pulmonary fibrosis. Donepezil inhibits acetylcholine (Ach) esterase, leading to higher Ach levels and corresponding downstream regulation of the Janus kinases (Jak)-Stat pathway [74]. It is noteworthy to mention that Jak-Stat pathway is an important regulator of Th17 differentiation, a key driver of pulmonary fibrosis [75]. Similarly, treatment with the bronchodilator, theophylline, led to reduced pulmonary fibrosis in the bleomycin mouse model via mechanism involving inhibition of IL-17 [76]. Specifically theophylline treatment led to inhibition of IL-6 induced RORγt transcription factor, which is critical for Th17 differentiation [76,77]. Acute kidney injury (AKI) often leads to lung inflammation including pulmonary fibrosis [78,79]. In a murine model of AKI induced lung fibrosis, treatment of rats with mycophenolate mofetil (MMF), an IL-17 antagonist showed a reduction of Th17 influx in lungs and improved outcome of pulmonary fibrosis [80].

6. B cells

B cells are part of the adaptive immune system and function through production of antibodies and cytokines and antigen presentation [81]. Mechanistically, B cells secrete a host of pro-fibrotic and pro-inflammatory factors which promote fibroblast activation and migration. These factors include IL-6, IL-8, and matrix metalloproteinase-7 (MMP-7) [82]. Not surprisingly, depletion of CD19+ plasma B cells attenuated bleomycin induced pulmonary fibrosis, whereas CD19 overexpression promoted pulmonary fibrosis [83]. Of the three FDA-approved drugs for the treatment of IPF, nintedanib and pirfendone, impair the cytokines secreted by B cells. This implicates the B-cell as a potential key therapeutic target whereby these two FDA-approved drugs regulate B-cell activity and in turn fibroblast migration [82]. One of the proposed mechanisms underlying the antifibrotic effect of nintedanib on B cells is because it affects the B-cell receptor (BCR) signaling [84]. There are also other drugs for targeting B cells. These include rituximab, an antibody in combination with therapeutic plasma exchange and intravenous immunoglobulin (Ig), has been reported for therapeutic treatment for AE in IPF patients by specifically targeting B cells [85]. In sharp contrast, a work by Moog et al. [86] showed that mice lacking mature B cells were not more resistant to bleomycin induced lung fibrosis than control mice. Clinically, various studies have shown that B cells number increases in the blood and lungs of IPF patients [87-90]. Chronic inflammation within the lungs leads to accumulation of lymphocytes and formation of ectopic germinal centers which are typically smaller than the lymphoid germinal centers [91]. These pulmonary germinal centers support diversification of B-cell responses and transports memory B cells into the lung tissues [91]. Interestingly, these B cells have been reported to specifically localize in the fibrotic loci of the lungs and the degree of fibrosis correlated with proportion of B-cell infiltration in the germinal center of the lungs [87,92]. There was a concurrent increase in CXCL13 (a cytokine which regulate B-cell homing) [93,94]. In IPF patients, CXCL13 negatively correlated with the DLCO score [95]. B-cell activating factor (BAFF) has also been reported to be high in the serum of IPF patients. The study by Vuga et al. [94] has also reported the correlation of CXCL13 with the outcome in IPF. The disease progression of IPF can be normally described in two stages-early IPF when the initial evaluation is done and late IPF for patients who have already undergone lung transplantation. B-cell numbers have been reported to be higher in both early and late IPF [96]. IPF patients also experience high percentage of autoreactive IgA B+ cells which correlated with disease progression [87].

Conclusion

Even though there are three FDA-approved drugs for the treatment of IPF, nintedanib, pirfenidone with the recent addition of nerandomilast in 2025 [97], the mean survival rate of IPF patients is very low due to steady decline of lung function [98]. The mean survival rate for IPF patients is 4.9 years for patients who are diagnosed incidentally and 3.9 years for patients who are not diagnosed incidentally [99]. A recent report suggested a mean survival rate of 5 to 7 years once the patient starts undergoing antifibrotic treatment [100]. Noteworthy to mention that FDA approved nerandomilast for IPF, about 10 years after nintedanib and pirfenidone were approved for the treatment of IPF. However, nerandomilast has various side effects such as diarrhea, upper respiratory tract infection, loss of appetite and weight, nausea, fatigue and vomiting. In addition to the three drugs mentioned above, there are numerous clinical trials ongoing for the treatment of IPF [101-106] with limited or no efficacy. However, A recent review has summarized all the current ongoing clinical trials for IPF with encouraging results [100]. Continued evaluation and follow-up will ultimately reveal the overall impact of these new therapies.

In this review, we have summarized how different subsets of lymphocytes synchronously act in the prognosis of pulmonary fibrosis. The adaptive immune system has long been targeted for the treatment of pulmonary fibrosis [26,85]. Some of these cell types such as NK, NKT/iNKT and Th1 cells prevent the development of pulmonary fibrosis whereas other cell types such as B-cell, Th2, and Th17 promote the development and progression of lung fibrosis. These lymphoid cells prevent or promote the development of fibrosis by interacting mostly with the mesenchyme and epithelial compartment. NK cells have been reported to reduce collagen expression in lung fibroblasts, specifically mediated by IFN-γ [22]. Activated iNKTs attenuate pulmonary fibrosis by reducing the burden of senescent fibroblast and epithelial cells [25]. Th1 cells, a potent secretor of IFN-γ, inhibits collagen synthesis in fibroblasts [50]. Supporting the antifibrogenic role of NK, iNKTs and Th1, γδ T cells localize in the interstitial space, secrete CXCL10 which in in turn inhibits fibroblast recruitment, promoting fibrosis resolution in the murine lung injury model [33]. γδ T cells have also been reported to clear senescent fibroblasts in the fibrotic lungs [34]. Not only fibroblast but also epithelial cells are regulated by γδ T cells. Epithelial cells are repaired slowly in γδ T knock out mice post injury with bleomycin [29]. In sharp contrast to the above cells, Th2 secreted IL-4 and IL-13 leads to myofibroblast differentiation from fibroblast and enhanced expressed of αSMA in fibroblast [107]. Th17 derived IL-17A has been reported to increase collagen (I and III) and αSMA in fibroblast, thereby leading to more deposition of ECM [74]. In addition to the above, B cells secrete vascular endothelial growth factor A (VEGFA) which is responsible for fibroblast migration and activation [82]. B cells also produce autoantibodies against epithelial antigens leading to further development of pulmonary fibrosis [87,108]. There are other lymphoid cells such as Tfh which indirectly regulate pulmonary fibrosis by acting on other cell types. For example, Tfh cells have been reported to act on B-cell proliferation, a key regulator of the disease [62]. An interesting aspect of these different cellular subsets is their dual role in pulmonary fibrosis. One such cell type is Treg cells which has different roles during the different phases of the injury, i.e., it has been reported to be both pro-fibrotic and anti-fibrotic [41]. Thus, Tregs acts as double-edged sword in the fibrotic niche. Whereas they are responsible for secreting Pdgf which directly stimulates the fibroblast [43] but on the other hand, they also inhibit the secretion of CXCL12 from epithelial cells during lung injury, thereby preventing the fibroblast recruitment [109]. Tregs have been reported to inhibit endothelial to mesenchymal transition (End-MT) by regulating bone morphogenetic protein receptor type 2 (BMPR2)110. EndMT leads to fibroblast accumulation within the fibrotic lung [111]. On a related note, the timing of the intervention of the disease and the relative role of the immune compartment in those phases also affect the outcome of pulmonary fibrosis [112].

Understanding the key mechanisms by which these immune cells are reprogrammed, how they interact with other immune cell types in different phases of the disease and finally, how these cohorts of immune cells synergistically interact with the mesenchyme will provide valuable insights into the pathogenesis of the disease. Naturally, the therapeutic aspect should be considered not by targeting a single immune cell but rather by targeting the interplay of the cohort of immune populations which together contribute to the pathophysiology of pulmonary fibrosis. Cutting edge technology such as single-cell RNA sequencing (ScRNA seq) could help us understand the mechanism of this interplay at the single cell level [113]. Use of precision cut lung slice imaging with IPF lungs also forms new prospect to test different therapeutics [114].

In this review, we have specifically focused on the bleomycin induced lung injury, the most common murine model for studying preclinical pulmonary fibrosis. An important caveat of the single injury bleomycin model is its natural resolution by day 56 post-injury [115] unlike IPF patients. There are murine models of repetitive bleomycin induced lung injury which partly mimics the repeated epithelial injury seen in IPF patients [116]. Additionally, there are other models of murine lung injury, such as, induced by asbestos, silica, radiation, and age dependent fibrosis with their own respective limitations [48].

In conclusion, while significant efforts have been made to state the complexity of immune compartments in pulmonary fibrosis, future research on understanding the key mechanism behind this complexity of immune cells interplay will pave the way for novel therapeutic approaches for IPF.

Notes

Authors’ Contributions

Conceptualization: Bhattacharyya A. Funding acquisition: Bhattacharyya A. Writing - original draft preparation: Bhattacharyya A. Writing - review and editing: all authors. Approval of final manuscript: all authors.

Conflicts of Interest

Julie D. Saba is co-founder of Sphinxion Therapeutics Inc., which develops gene therapy for individuals with SPLIS. Julie D. Saba is an author on patent International Application Serial No. PCT/US2021/018613, ‘Adeno-Associated Viral (Aav)-Mediated SGPL1 Gene Therapy for Treatment of Sphingosine-1-Phosphate Lyase Insufficiency Syndrome (SPLIS)’ published on 08/26/2021 and assigned publication number WO 2021/168140. Aritra Bhattacharyya declares no conflict of interest.

Acknowledgments

The figure was created in https://BioRender.com with the agreement number-BJ28MWNN1X.

Funding

The work is supported by CPDA funding from Indian Statistical Institute, Kolkata (Aritra Bhattacharyya). Julie D. Saba is supported by grant from NICHD (1R01HD113778-01).

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Fig. 1.

Fig. 1.

Overview of lymphocyte-mesenchyme interaction in a fibrotic lung. Red and green arrows indicate overall inhibition and promotion of pulmonary fibrosis respectively. Tfh: T follicular helper; Treg: regulatory T; IL: interleukin; Th: T helper; IFN-γ: interferon-γ; TGF-β: transforming growth factor-β; MMP-7: matrix metalloproteinase-7; Auto Ab: autoreactive antibodies; NK: natural killer; NKT: natural killer T.

Table 1.

Incidence rate of idiopathic pulmonary fibrosis in different parts of the world

Name of the country Incidence rate (every 100,000 people) Reference
European Union 25.1 [4]
Asia (Japan, Taiwan, South Korea, and China) 1.2–4.16 [5,6]
USA 29.8 [4]
Canada 18.7 [7]

Table 2.

Summary of secreted factors from lymphoid cells in the fibrotic niche

Type of immune cells Key secretory factors in lung fibrosis Regulation of non-immune cells in the lungs
Natural killer cells IFN-γ Fibroblasts
Invariant natural killer T cells (type I) IFN-γ, IL-4, IL-17A Fibroblasts, epithelial cells
Natural killer T cells (type II) IFN-γ Fibroblasts
γδ T cells IL-17A Fibroblasts, epithelial cells
Regulatory T cells Platelet-derived growth factor (Pdgf), TGF-β Fibroblasts, epithelial cells, endothelial cells
Helper T cells (Th1, Th2, Th17, Tfh) IL-2, IL-4, IL-5, IL-6, IL-12, IL-13, IL-17, IL-18, IL-21, IFN-γ Fibroblasts
B cells IL-6, IL-8, MMP-7, Auto Ab Fibroblast, epithelial cells

IFN-γ: interferon-γ; IL: interleukin; TGF-β: transforming growth factor-β; Th: T helper; Tfh: T follicular helper; MMP-7: matrix metalloproteinase-7; Auto Ab: autoreactive antibodies.