Cytotoxic CD4 Development Requires CD4 Effectors to Concurrently Recognize Local Antigen and Encounter Infection-Induced IL-15

Abstract

SummaryT follicular helper (TFH) and Cytotoxic CD4 (ThCTL) are tissue-restricted CD4 effector subsets, functionally specialized to mediate optimal Ab production and cytotoxicity of infected cells. Influenza infection generates robust CD4 responses, including lung ThCTL and SLO TFH, that protect against reinfection by variant strains. Antigen (Ag) presentation after infection, lasts through the effector phase of the response. Here, we show that this effector phase Ag presentation, well after priming, is required to drive CD4 effectors to ThCTL and TFH. Using in vivo influenza models, we varied Ag presentation to effectors acutely, just at the effector phase. Ag presentation was required in the tissue of effector residence. We suggest these requirements contain unnecessary or potentially pathogenic CD4 responses, only allowing them if infection is uncleared. The results imply that providing effector phase Ag, would lead to stronger humoral and CD4 tissue immunity and thus can be applied to improve vaccine design.

“An Intrinsic Program Determines Key Age-Associated Changes in Adaptive Immunity That Limit Response to Non-Pathogens”

“…We find that even in the young, development of CD4 memory and TFH cells depend on high levels of antigen presentation and PR signals that persist into the CD4 effector stage (Bautista et al, 2016;Devarajan et al, 2018;Devarajan et al, 2020;Xia et al, 2020) and on antigen presentation in sites of memory development (Devarajan et al, 2020). We predict the aged may need higher levels of these to induce protection.…”

“…Ongoing infection is also necessary. Thus high systemic PR signals are needed both to activate the APC to drive TFH development and to induce yetto-be determined innate pathways (Devarajan et al, 2018;Devarajan et al, 2020). While these studies are in young mice, we predict these PR signals will be of equal or greater importance in aged mice, due to the need for higher IL-6 levels to stimulate aged naïve T cells (Figure 1B).…”

“…Indeed, adding activated APC at the effector phase enhances memory generation to inactivated influenza (Xia et al, 2020). Moreover, to drive further TFH effector responses, Ag on activated APCs needs to be present locally where the TFH reside (Devarajan et al, 2018;Devarajan et al, 2020). Ongoing infection is also necessary.…”