The highs and lows of CD4+ tissue-resident T cells in lung fibrosis

Chronic exposure to fungal antigen drives the development of two subsets of CD4+ TRM cells, distinguished by high or low expression of the integrin CD103, with opposing roles in inflammation-induced lung fibrosis.

Tissue-resident memory T cells (TRM cells) are a subset of T cells that are critically involved in the immunosurveillance of peripheral tissues during infection and cancer1. Although substantial effort has defined the properties of CD8+ TRM cells, the understanding of CD4+ TRM cells is comparatively limited. In this issue of Nature Immunology, Ichikawa et al. identify two distinct subsets of lung-resident CD4+ T cells during chronic inflammation: a pathogenic CD103lo population that promotes tissue fibrosis, and a protective CD103hi regulatory T cell (Treg cell) subset that keeps this process in check2.

Memory T cells can be divided into two categories by virtue of their tissue trafficking and functional properties. Circulating memory T cells survey the blood and lymphoid organs, whereas TRM cells are strategically positioned within peripheral tissues, where they provide local immune protection after reinfection. Akin to their CD8+ counterparts, CD4+ TRM cells have been suggested to be beneficial in the context of infection, during which they can secrete cytokines such as IFN-γ that facilitate viral clearance after re-exposure to the pathogen1. On the other hand, studies have also linked CD4+ TRM cells to pathological autoimmune responses during colitis and asthma3,4. Thus, in the context of disease, CD4+ TRM cells probably play either helpful roles or deleterious roles, although what contributes to these opposing contributions has not been defined until now.

To assess CD4+ T cell responses, Ichikawa et al. repeatedly exposed mice to antigens derived from Aspergillus fumigatus2, a fungus associated with severe persistent asthma. Chronic stimulation with Aspergillus antigen results in inflammation-induced lung fibrosis, accompanied by an increase in effector cytokines and infiltration of immune cells around the bronchi. One key observation in this chronic-antigen-stimulation model is substantial infiltration into the lung parenchyma of CD4+ T cells with variable expression of the surface molecules CD69 and CD103, two markers that have been associated with tissue residency. RNA sequencing of the various CD4+ T cell populations in the inflamed lungs shows that CD69+CD103lo and CD69+CD103hi CD4+ T cells downregulate genes encoding molecules involved in tissue egress (S1pr1, Klf2 and Ccr7) and upregulate Cxcr6 (which encodes the chemokine receptor CXCR6), consistent with a tissue-resident phenotype. Furthermore, both CD103lo cells and CD103hi cells show increased expression of genes encoding fibrosis-related molecules, suggestive of a more predominant role for these two populations in lung inflammation than that of their circulating CD4+ T cell counterparts. Classic parabiosis experiments show that CD4+ T cells in the lungs of Aspergillus antigen–exposed mice do not equilibrate via the blood, which confirms that these cells are indeed a long-term resident population.

Notably, the authors observe that the CD103lo and CD103hi tissue-resident populations in the lung are functionally distinct. The production of effector cytokines, including IL-4, IL-5, IL-13 and IL-17A, is restricted mostly to the CD103lo subset, which is associated with the pathology of fibrotic responses in the lungs. The CD103hi population expresses genes, including Foxp3, Klrg1 and Prdm1 (which encodes the transcription factor Blimp-1), that are characteristic of Treg cells. Strikingly, antibody-mediated depletion of the CD103hi tissue-resident Treg cell population is shown to significantly aggravate fibrosis (Fig. 1). Together these data provide evidence of functional diversity between different tissue-resident CD4+ TRM cells in the lungs during chronic inflammation-induced fibrosis. This includes T cell populations that act in an opposing manner, with the CD103lo population acting as a driver of disease and the CD103hi population forming a classical anti-inflammatory regulatory subset that dampens the inflammatory response.

Fig. 1: CD103hi tissue-resident Treg cells control fibrotic responses elicited by CD103lo pathogenic CD4+ TRM cells in the lungs.

Chronic exposure to A. fumigatus antigen promotes the development of two types of CD4+ TRM cells in the lung parenchyma. Pathological CD69+CD103lo CD4+ TRM cells (‘Path’ helper T cells) secrete pro-inflammatory cytokines (IL-4, IL-5, IL-13 and IL-17A) that drive tissue fibrosis and deposition of collagen around the bronchi. CD69+CD103hi tissue-resident Treg cells limit tissue pathology. Depletion of CD103hi tissue-resident Treg cells exacerbates inflammation-induced lung fibrosis.

What remains undefined are the mechanisms that select between functionally distinct CD4+ T cell populations in this model of disease. It is known that the fibrosis-associated cytokine TGF-β can induce expression of the transcription factor FoxP3 by CD4+ Treg cells as well as that of CD103, which is the identifying feature of this population. Therefore, one could speculate that fibrosis might contribute to the generation of Treg cells in a TGF-β-dependent manner to drive a negative feedback loop that limits tissue damage elicited by other immune cell populations within the lungs. Regardless, the findings of this study clearly link TRM cells to tissue pathology, with distinct subsets contributing to the amelioration or aggravation of disease. Several strategies could be implemented to remove pathogenic TRM cells from tissues. Although CD8+ TRM cells are generally found in association with epithelial cells, CD4+ TRM cells are often found in clusters with other immune cells. CD4+ TRM cells can be retained in these aggregates via production of CCL5, with blockade of this chemokine sufficient to disrupt clusters of immune cells, which results in the loss of CD4+ TRM cells5,6. In the lungs, inflammation caused by infection or an allergic reaction drives the generation of ectopic lymphoid structures called ‘inducible bronchus-associated lymphoid tissues’. The authors of the present study2 previously found, in a model of allergic asthma, that pathogenic cells of the TH2 subset of helper T cells are maintained within those structures and that disruption of the structures leads to the disappearance of these cells7. Nonetheless, disruption of clusters of immune cells could represent a promising method for the removal of pathogenic CD4+ TRM cells from tissues. Another approach is to target factors necessary for the maintenance of TRM cells, such as the local blockade of cytokines, including IL-2 or IL-7, shown to be required for the development of lung CD4+ TRM cells in various settings4,7,8. When placed in the context of this current study, blockade of IL-7 might be a possible way to eliminate pathogenic CD4+ TRM cells without targeting resident Treg cells with low expression of its receptor, IL-7R.

A growing body of evidence suggests that the development of memory T cells is influenced by a multitude of factors, including cellular origin (CD4+ T cells versus CD8+ T cells), migratory properties (circulating cells versus tissue-resident cells) and exposure to factors within the tissue microenvironment. In addition to those levels of regulation, priming conditions may add another layer of complexity that results in the differentiation into distinct lineages (TH1 cells, TH2 cells, TH17 cells and Treg cells, in the case of CD4+ T cells). For example, a study has demonstrated the co-existence of two types of skin CD8+ TRM cells that produce either IFN-γ or IL-17A; the cells were primed by different dendritic cells subsets following association with the commensal Staphylococcus epidermidis9. This indicates that T cell interactions that precede the formation of TRM cells may also play a part in shaping the establishment of functional diversity within tissues.

Collectively, the work by Ichikawa et al. demonstrates that distinct CD4+ TRM cell subsets with fundamentally opposing roles can co-exist within the same tissue2. Future studies will be needed to establish the defining features of different tissue-resident populations and to elucidate the mechanisms that drive functional heterogeneity during health and disease.


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Correspondence to Laura K. Mackay.

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Evrard, M., Mackay, L.K. The highs and lows of CD4+ tissue-resident T cells in lung fibrosis. Nat Immunol 20, 1416–1418 (2019). https://doi.org/10.1038/s41590-019-0501-3

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