Functional Impairment of 'Helpless' CD8  Memory T Cells is Transient and Driven by Prolonged But Finite Cognate Antigen Presentation

Abstract

Generation of functional CD8+ T cell memory typically requires engagement of CD4+ T cells. However, in certain scenarios, such as acutely-resolving viral infections, effector (TE) and subsequent memory (TM) CD8+ T cell formation appear impervious to a lack of CD4+ T cell help during priming. Nonetheless, such “helpless” CD8+ TM respond poorly to pathogen rechallenge. At present, the origin and long-term evolution of helpless CD8+ T cell memory remain incompletely understood. Here, we demonstrate that helpless CD8+ TE differentiation is largely normal but a multiplicity of helpless CD8+ TM defects, consistent with impaired memory maturation, emerge as a consequence of prolonged yet finite exposure to cognate antigen. Importantly, these defects resolve over time leading to full restoration of CD8+ TM potential and recall capacity. Our findings provide a unified explanation for helpless CD8+ T cell memory and emphasize an unexpected CD8+ TM plasticity with implications for vaccination strategies and beyond.

Note:
Funding Information: This research was supported by German Research Foundation (DFG) research fellowship HE 7559/1-1 (V.v.d.H.); NIH T32 training grants AI052066 and DK007792 (B.D.); NIH grants R21AI121840, R21AI169789 and RO1AI142985 (J.C.-d.l.T.); and NIH grants R01AI093637 and R01DK130425 (D.H.)

Declaration of Interests: The scRNAseq analyses in this study were partially paid for by Cytek Biosciences, USA. The authors declare no other competing interests.

Ethical Approval Statement: All procedures were approved by the e Icahn School of Medicine at Mount Sinai (ISMMSA) Institutional Animal Care and Use Committee, and all efforts were made to minimize animal suffering.

Keywords: CD8 T cell memory, CD4 T cell help, helpless CD8 T cell memory, acute viralinfection, lymphocytic choriomeningitis virus, CD8 T cell memory maturation