Secondary infections rejuvenate the intestinal CD103 ⁺ tissue-resident memory T cell pool

Abstract

Resident T lymphocytes (T RM ) protect tissues during pathogen reexposure. Although T RM phenotype and restricted migratory pattern are established, we have a limited understanding of their response kinetics, stability, and turnover during reinfections. Such characterizations have been restricted by the absence of in vivo fate-mapping systems. We generated two mouse models, one to stably mark CD103 + T cells (a marker of T RM cells) and the other to specifically deplete CD103 − T cells. Using these models, we observed that intestinal CD103 + T cells became activated during viral or bacterial reinfection, remained organ-confined, and retained their original phenotype but failed to reexpand. Instead, the population was largely rejuvenated by CD103 + T cells formed de novo during reinfections. This pattern remained unchanged upon deletion of antigen-specific circulating T cells, indicating that the lack of expansion was not due to competition with circulating subsets. Thus, although intestinal CD103 + resident T cells survived long term without antigen, they lacked the ability of classical memory T cells to reexpand. This indicated that CD103 + T cell populations could not autonomously maintain themselves. Instead, their numbers were sustained during reinfection via de novo formation from CD103 − precursors. Moreover, in contrast to CD103 - cells, which require antigen plus inflammation for their activation, CD103 + T RM became fully activated follwing exposure to inflammation alone. Together, our data indicate that primary CD103 + resident memory T cells lack secondary expansion potential and require CD103 − precursors for their long-term maintenance.

Sepsis-induced changes in differentiation, maintenance, and function of memory CD8 T cell subsets

“…and Fung et al. showed that CD103 + T RM cells have limited proliferation capacity, but CD103 - T RM cells undergo robust expansion upon Ag re-encounter, further highlighting the heterogeneity within T RM pool ( 121 , 122 ). Nonetheless, successive Ag exposures improve the longevity and protective function of T RM pool; for example, 4° influenza-specific T RM cells show enhanced durability and heterosubtypic immunity than 1° T RM cells ( 123 ).…”

Advances and challenges in studying the tissue‐resident T cell compartment in the human female reproductive tract

“…A set of recent mouse model studies used elegant fate-mapping approaches to assess how intestinal T RM respond to TCR-mediated reactivation. 84,85 These CD8 T-cell-focused studies found that CD103+ T RM cells had fairly limited responses to TCRmediated reactivation. We hypothesize that a similar level of T RM hyporesponsiveness may exist in the FRT, helping to maintain T RM homeostasis during inflammatory episodes.…”

“…Of note, this baseline level of inflammation appears to be critical for maintenance of barrier immunity (“inflammatory surveillance”). A set of recent mouse model studies used elegant fate‐mapping approaches to assess how intestinal T RM respond to TCR‐mediated reactivation 84,85 . These CD8 T‐cell‐focused studies found that CD103+ T RM cells had fairly limited responses to TCR‐mediated reactivation.…”

Tissue-resident memory T cells in gastrointestinal tumors: turning immune desert into immune oasis

“…For instance, in the intestine, CD103 + CD69 + CD8 + Trm cells possess high ability to produce inflammatory cytokines, while CD103 - CD69 + CD8 + Trm cells have a high expression of β2-integrin and are more able to produce granzyme ( 28 ). Besides, researchers have found that CD103 - Trm can differentiate into CD103 + Trm to mediate immune response towards secondary infections, instead of the primarily resident CD103 + Trm ( 29 , 30 ). Besides the different function, various subsets of Trm cells, including CD103 + CD69 + , CD103 - CD69 + and CD103 - CD69 - Trm cells, have shown great potential to proliferate.…”