Mucosal Resident Memory CD4 T Cells in Protection and Immunopathology

Abstract

Tissue-resident memory T cells (TRM) comprise a newly defined subset, which comprises a major component of lymphocyte populations in diverse peripheral tissue sites, including mucosal tissues, barrier surfaces, and in other non-lymphoid and lymphoid sites in humans and mice. Many studies have focused on the role of CD8 TRM in protection; however, there is now accumulating evidence that CD4 TRM predominate in tissue sites, and are integral for in situ protective immunity, particularly in mucosal sites. New evidence suggests that mucosal CD4 TRM populations differentiate at tissue sites following the recruitment of effector T cells by local inflammation or infection. The resulting TRM populations are enriched in T-cell specificities associated with the inducing pathogen/antigen. This compartmentalization of memory T cells at specific tissue sites may provide an optimal design for future vaccination strategies. In addition, emerging evidence suggests that CD4 TRM may also play a role in immunoregulation and immunopathology, and therefore, targeting TRM may be a viable therapeutic approach to treat inflammatory diseases in mucosal sites. This review will summarize our current understanding of CD4 TRM in diverse tissues, with an emphasis on their role in protective immunity and the mechanisms by which these populations are established and maintained in diverse mucosal sites.

Tissue-Specific Control of Tissue-Resident Memory T Cells

“…Similar as CD4 + T RM clusters in the skin and vagina, clusters of lung CD4 + T RM have been identified after influenza virus infection, 170 suggesting a common mechanism underlying CD4 + T RM differentiation and/or maintenance. In contrast to lung CD8 + T RM cells, one report has suggested that mouse lung CD4 + T RM is TGF-β-independent, consistent with a CD103 − phenotype.…”

“…CD4 + T RM cells represent a critical adaptive component of local immunity. 170 We will use the last section to summarize the recent findings about CD4 + T RM cells in various tissues. We will not include Foxp3 + regulatory T cells in our discussion as recent reviews have covered the related findings.…”

“…27,28,67,152,177,178 Comparing with CD8 + lung T RM , CD4 + T RM cells usually carry less CD103 or express CD11a instead of CD103. 170,178,179 Genome wide transcriptional analysis reveals that CD4 + lung T RM cells resemble CD8 + lung T RM cells. 151,152,179 Similar transcription programs including the down-regulation of T-bet and Eomes, and the up-regulation of Blimp-1 and Notch signaling, direct the local differentiation of lung CD4 + T RM cells.…”

Intranasal Introduction of Fc-Fused Interleukin-7 Provides Long-Lasting Prophylaxis against Lethal Influenza Virus Infection

“…It is well known that IAV-specific memory CD4 T cells contribute to develop protective immune responses against respiratory viral infection (42). On the one hand, typical secondary recall responses to antigens by memory CD4 T cells in the lung participate in direct viral clearance (43).…”

Emerging concepts in tissue-resident T cells: lessons from humans

“…Studies in mouse models of infection have used T cell adoptive transfers [25, 26], parabiosis (surgical conjoining of two mice to create shared circulation) [22], and intravenous infusion of fluorescent antibodies to label T cells in circulation versus those within tissues [27] to distinguish between these possibilities. In mice, tissue T cells comprise both circulating and tissue resident memory T cells (TRM), with TRM found in multiple sites including lungs, intestines, skin, vaginal mucosa, liver, intestines, and to lesser extents in lymph nodes [26–31]. These non-migratory TRM can be generated from site-specific infection in skin, lungs, and vaginal mucosa, and are specifically retained within these sites [26, 32–35].…”