Functional Dynamics of Cytotoxic CD4+ T cells in Acute and Chronic Viral Infections 2259913

Abstract Introduction Classically CD4+ T cells are recognized for their helper functions in coordinating adaptive immunity; however recent studies have identified a unique subset of antigen experienced CD4+ T cells which acquire cytotoxic potential evidenced by their ability to eliminate MHC II+ targets in vivo. Though these cytotoxic CD4+ T cells (CD4 CTLs) play a crucial role in various chronic viral infections and cancers, the regulation of their function and in vivo target specificity remain unclear. Methods To study CD4 CTL dynamics, we used a well established mice model of acute (Armstrong) and chronic (Clone 13) LCMV infection. Results We demonstrate that both acute and chronic LCMV infections rapidly induce a subset of granzyme B and perforin-expressing Th1 cells with in vivo cytotoxic function. These cells are detectable as early as 48 hrs post-infection, and their killing activity is in part perforin-dependent. Intriguingly, in contrast to the sustained cytotoxic activity seen in acute infection, chronic infection triggers a progressive decline in CD4 CTL killing ability in vivo, that is restored upon PD-L1 blockade. The early killing activity suggested that these cells might regulate antigen presentation during infection. Using a 1:1 Wildtype:MHC II-/- bone marrow chimera model we show that MHC II-/- DCs (which are immune to CD4 CTL killing but susceptible to CD8 T cell and NK cell killing) undergo initial immune-mediated killing similar to WT DCs by 60 hours post LCMV-infection. However, by Day 9 of chronic LCMV infection a higher proportion of MHC II-/- CD8α+ DCs were LCMV-infected compared to wildtype CD8α+ DCs in the same mice, suggesting that CD4 CTLs play a role in limiting viral infection in this specific DC subset during chronic viral infection. Conclusion In conclusion, our study provides new insights into the dynamics of CD4 CTLs during acute and chronic viral infections, and begins to define their specific target cells in vivo. Funding Source Showalter Trust Foundation award, the Indiana CTSI and funds from IUSCCC and IU CCEH Topic Categories Viral Immunology (VIR)