The Memory Inflation Response Against Spread‐Defective CMV Requires Priming‐Independent CD4 ⁺ T Cell Help

Memory inflation (MI) is a distinctive CD8 + T cell response to chronic cytomegalovirus (CMV) infection, characterized by non‐contracting, functional populations that are predominantly effector differentiated. Harnessing such responses has received growing attention as a promising vaccination strategy, using spread‐defective CMV‐vectors. However, many underlying mechanistic aspects of CD8 + MI responses, including their dependency on CD4 + T cell help, remain unclear. Using a Rag KO transfer model, we demonstrate that CD4 + T cells enhance effector differentiation of inflationary CD8 + T cells when present during priming, or when introduced at late timepoints post‐infection, indicating a continuous, priming‐independent support mechanism. This helper requirement was specific to spread‐defective CMV infection, whereas spread‐competent virus induced MI even in the absence of CD4 + T cells. We confirmed the importance of continuous support in wild‐type mice, where late CD4 depletion attenuated an established MI response. Gene set enrichment analysis implicates IFNγ, TNF, and IL‐1 signaling as potential mediators of CD4 + T cell support. Our findings clarify CD4 + T cell help requirements for maintaining effector populations in MI during chronic antigen exposure. These results have particular relevance for spread‐defective CMV‐based vaccination strategies and T cell‐based therapies in which the persistence and expansion characteristic of MI are desirable qualities.