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TISSUE-RESIDENT T CELLSThe 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 highor low expression of the integrin CD103, with opposing roles in inflammation-induced lung fibrosis.

Maximilien Evrard and Laura K. MackayTissue-resident memory T cells(TRM cells) are a subset of T cells
that are critically involved in theimmunosurveillance of peripheral tissues
during infection and cancer1. Althoughsubstantial effort has defined the properties
of CD8+ TRM cells, the understanding ofCD4+ TRM cells is comparatively limited. In
this issue of Nature Immunology, Ichikawa
et al. identify two distinct subsets of lungresident CD4+ T cells during chronic
inflammation: a pathogenic CD103lo popu­
lation that promotes tissue fibrosis, and aprotective 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 theblood and lymphoid organs, whereas TRM
cells are strategically positioned within
peripheral tissues, where they provide local
immune protection after reinfection. Akinto their CD8+ counterparts, CD4+ TRM cells
have been suggested to be beneficial in thecontext of infection, during which they cansecrete cytokines such as IFN-γ that facilitate
viral clearance after re-exposure to thepathogen1. On the other hand, studies havealso linked CD4+ TRM cells to pathologicalautoimmune responses during colitis andasthma3,4. Thus, in the context of disease,
CD4+ TRM cells probably play either helpfulroles or deleterious roles, although whatcontributes 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 withAspergillus antigen results in inflammationinduced lung fibrosis, accompanied by anincrease in effector cytokines and infiltrationof immune cells around the bronchi. One
key observation in this chronic-antigenstimulation model is substantial infiltration
into the lung parenchyma of CD4+ T cellswith 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 andCD69+CD103hi CD4+ T cells downregulate
genes encoding molecules involved in tissueegress (S1pr1, Klf2 and Ccr7) and upregulate
Cxcr6 (which encodes the chemokine
receptor CXCR6), consistent with a tissueresident phenotype. Furthermore, bothCD103lo cells and CD103hi cells show
increased expression of genes encoding
fibrosis-related molecules, suggestive ofa more predominant role for these twopopulations in lung inflammation than thatof 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 theCD103lo and CD103hi tissue-resident
populations in the lung are functionallydistinct. The production of effector
cytokines, including IL-4, IL-5, IL-13
and IL-17A, is restricted mostly to theCD103lo subset, which is associated with thepathology of fibrotic responses in the lungs.
The CD103hi population expresses genes,
including Foxp3, Klrg1 and Prdm1 (whichencodes the transcription factor Blimp-1),
that are characteristic of Treg cells. Strikingly,
antibody-mediated depletion of the CD103hi
tissue-resident Treg cell population is shownto significantly aggravate fibrosis (Fig. 1).
Together these data provide evidence offunctional diversity between different tissueresident 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 andthe CD103hi population forming a classicalanti-inflammatory regulatory subset thatdampens the inflammatory response.

Nature Immunology | www.nature.com/natureimmunology

What remains undefined are themechanisms that select between functionallydistinct CD4+ T cell populations in thismodel of disease. It is known that thefibrosis-associated cytokine TGF-β caninduce expression of the transcription factor
FoxP3 by CD4+ Treg cells as well as that ofCD103, which is the identifying featureof this population. Therefore, one could
speculate that fibrosis might contributeto the generation of Treg cells in a TGFβ-dependent manner to drive a negative
feedback loop that limits tissue damage
elicited by other immune cell populations
within the lungs. Regardless, the findingsof this study clearly link TRM cells to tissue
pathology, with distinct subsets contributing
to the amelioration or aggravation ofdisease. Several strategies could beimplemented 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 inclusters with other immune cells. CD4+ TRM
cells can be retained in these aggregates via
production of CCL5, with blockade of thischemokine sufficient to disrupt clusters ofimmune cells, which results in the loss ofCD4+ TRM cells5,6. In the lungs, inflammation
caused by infection or an allergic reaction
drives the generation of ectopic lymphoidstructures called ‘inducible bronchusassociated lymphoid tissues’. The authorsof the present study2 previously found, in amodel of allergic asthma, that pathogenic
cells of the TH2 subset of helper T cells aremaintained within those structures andthat disruption of the structures leads to thedisappearance of these cells7. Nonetheless,disruption of clusters of immune cells
could represent a promising method forthe 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news & views(circulating cells versus tissue-resident cells)
and exposure to factors within the tissue
microenvironment. In addition to thoselevels 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 theco-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 thecommensal Staphylococcus epidermidis9.
This indicates that T cell interactions thatprecede the formation of TRM cells may also
play a part in shaping the establishment offunctional diversity within tissues.
Collectively, the work by Ichikawa
et al. demonstrates that distinct CD4+ TRM
cell subsets with fundamentally opposingroles can co-exist within the same tissue2.
Future studies will be needed to establish
the defining features of different tissueresident populations and to elucidate
the mechanisms that drive functional
heterogeneity during health and disease. ❐Airways

Epithelium

Collagen

Fibroblast

CD103lo CD4+ TRM cells'Path' helper T cells

CD103hi CD4+ TRM cells
Treg cells

IL-4, IL-5, IL-13,
IL-17A

Parenchyma

CD103lo CD4+ TRM cells'Path' helper T cells

CD103hi CD4+ TRM cells
Treg cells

Maximilien Evrard andLaura K. Mackay *IL-4, IL-5, IL-13,
IL-17A

Naive
CD4+ T cells

Activated
CD4+ T cells

Department of Microbiology and Immunology, TheUniversity of Melbourne, The Peter Doherty Institutefor Infection and Immunity, Melbourne, Victoria,Australia.
*e-mail: lkmackay@unimelb.edu.au

BloodFig. 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 typesof CD4+ TRM cells in the lung parenchyma. Pathological CD69+CD103lo CD4+ TRM cells (‘Path’ helperT cells) secrete pro-inflammatory cytokines (IL-4, IL-5, IL-13 and IL-17A) that drive tissue fibrosis anddeposition 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.

context of this current study, blockade ofIL-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 suggeststhat 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

Published: xx xx xxxx
https://doi.org/10.1038/s41590-019-0501-3
References

1. Masopust, D., Soerens, A. G. & Tissue-Resident, T. Annu. Rev.
Immunol. 37, 521–546 (2019).
2. Ichikawa, T.et al. Nat. Immunol. https://doi.org/10.1038/s41590019-0494-y (2019).
3. Zundler, S. et al. Nat. Immunol. 20, 288–300 (2019).
4. Hondowicz, B. D. et al. Immunity 44, 155–166 (2016).
5. Iijima, N. & Iwasaki, A. Science 346, 93–98 (2014).
6. Collins, N. et al. Nat. Commun. 7, 11514 (2016).
7. Shinoda, K. et al. Proc. Natl Acad. Sci. USA 113, E2842–E2851(2016).
8. McKinstry, K. K. et al. Nat. Commun. 5, 5377 (2014).
9. Naik, S. et al. Nature 520, 104–108 (2015).

Competing interests

The authors declare no competing interests.

Nature Immunology | www.nature.com/natureimmunology