IL-15 supports the generation of protective lung-resident memory CD4 T cells

Abstract

Tissue-resident memory T cells (TRM) provide optimal defense at sites of infection, but signals regulating their development are unclear, especially for CD4 T cells. Here, we identify two distinct pathways that lead to the generation of CD4 TRM in the lungs following influenza infection. The TRM are transcriptionally distinct from conventional memory CD4 T cells, and share a gene signature with CD8 TRM. The CD4 TRM are superior cytokine producers compared to conventional memory cells, can protect otherwise naïve mice against a lethal influenza challenge, and display functional specialization by inducing enhanced inflammatory responses from dendritic cells compared to conventional memory cells. Finally, we demonstrate than an IL-2-dependent and a novel IL-2-independent but IL-15-dependent pathway support the generation of cohorts of lung TRM.

Tissue-Specific Control of Tissue-Resident Memory T Cells

“…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.…”

“…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. 152 Interestingly, human and mouse infant T cells (including both CD4 + and CD8 + T cells) express enhanced levels of T-bet and exhibit defective lung T RM cell formation, further suggesting that down-regulation of T-bet is a conserved common mechanism underlying both CD4 + and CD8 + T RM differentiation.…”

“…Distinct from CD103 + CD8 + T RM , IL-15 is required during the early differentiation, but not the long-term maintenance of CD4 + lung T RM cells in mouse. 179 Following both acute viral infection (a Th1 response) and brief allergy exposure-induced lung inflammation (a Th2 response), a clear population of lung-resident antigen-specific CD4 + T cells that is separated from bloodstream forms in an IL-2-dependent manner and play essential functions in local immunity. 180,181 In response to prolonged allergen exposure, a similar CD69 + and Th2-biased CD4 + T RM population persists in the lung parenchyma.…”

Fucosyltransferase Induction during Influenza Virus Infection Is Required for the Generation of Functional Memory CD4+ T Cells

“…To determine if WT and Fut4/7 −/− OT-II were differentially distributed in the vasculature versus parenchyma lungs, which could potentially account for differences in survival factor usage (29). Thus, WT or Fut4/7 −/− OT-II T cells were co-injected into WT hosts and infected with PR8-OVA II .…”

Origins of CD4+ circulating and tissue‐resident memory T‐cells

“…The lungs contain a population of CD4 + T RM that have been shown to play a critical role in recruiting CD8 + T‐cells and enhancing secondary immune responses against bacterial, viral and worm infections . In an influenza infection model, antigen‐specific memory CD4 + T‐cells migrate to the lungs and are retained in the tissue without recirculation, as demonstrated by parabiosis experiments .…”