Post Doctoral Fellow Indiana Univ. Sch. of Med. Indianapolis, Indiana, United States
Disclosure(s):
Prakash K. Sahoo, PhD: No financial relationships to disclose
Introduction/Rationale: 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-/- CD8+ DCs were LCMV-infected compared to wildtype CD8+ 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.
