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Stem-like precursors of helper T cells dependent on Eomes and Myb sustain CD4+ T cell responses during chronic infection

ABSTRACT: CD4+ T helper cells are critical for sustaining adaptive immunity against infection. However, the factors that regulate their maintenance and function in response to protracted infections remain poorly understood. Here, using the Lymphocytic Choriomeningitis Virus (LCMV) model, we identify a transcriptionally defined population of CD4+ helper T cells, which manifest in chronic but not acute infection, to be essential to sustain chronic CD4+ T cell immunity. These cells, which are distinct from memory-like CD4+ T cells, express markers typically associated with exhausted T cells, including PD-1 and TOX, and can self-renewal and give rise to both type 1 T helper (Th1) and follicular T helper (Tfh) cells, thus acting as precursors of T helper (pTh) cells. These cells also mediate the Th1-biased differentiation and expansion in response to PD-1-targeted immune checkpoint blockade (ICB). Molecularly, we show that the development, function and maintenance of pTh cells depend on the transcription factors EOMES and MYB, respectively. While EOMES instructs the overall pTh transcriptional program and the subsequent progression into mature T helper cells, MYB preserves pTh cells by limiting their downstream differentiation. Consequently, the maintenance of both Th1 and Tfh responses is severely compromised in CD4+ T cells lacking either EOMES or MYB. Thus, our findings reveal a precursor-progeny hierarchy in CD4+ T cells and its molecular underpinnings that sustain long-term helper response specifically in chronic infection and during immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE283820 | GEO | 2026/06/09

REPOSITORIES: GEO

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