Back to publications

2026

Immunity 2026 Jun 24:S1074-7613(26)00231-1. doi: 10.1016/j.immuni.2026.06.001.

Stem-like precursors of exhausted Th cells upheld by a Tox-Myb-Eomes transcriptional hierarchy propagate Th cell responses in chronic infection

Lifen Wen, Chun-Hsi Su, Nikita Potemkin, Lachlan Dryburgh, Lei Qin, Sining Li, Marcela De Lima Moreira, Ashraful Haque, Xiye Sun, Vincenzo Cinella, Jan Schroeder, Carlson Tsui, Axel Kallies

Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. Computational Sciences Initiative (CSI), The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia. Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia; Garvan Institute of Medical Research, Darlinghurst, NSW, Australia. Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia; Institute of Molecular Medicine & Experimental Immunology, University Hospital Bonn, Bonn, Germany.

Service type: Stock strains

Abstract

CD4+ T helper (Th) cells are critical drivers of adaptive immunity, but how their responses are maintained during chronic infection remains unclear. Here, we identified a population of CD4+ T cells that expressed CD62L and the inhibitory receptor PD-1 and exhibited both features of exhaustion and stemness. These cells acted as precursors of T helper (pTh) cells and sustained Th cell immunity during chronic lymphocytic choriomeningitis virus (LCMV) infection, giving rise to type 1 (Th1) and follicular T helper (Tfh) cells and cytotoxic-like T cells. pTh cells developed under conditions of high antigen exposure and depended on exhaustion and stemness-associated transcription factors TOX, EOMES, and MYB. Consequently, the maintenance of mature Th cells was severely compromised when CD4+ T cells lacked these factors. pTh cells also contributed to Th1 cell expansion upon PD-1 blockade. Overall, our findings reveal a molecular program and cellular hierarchy that preserve long-term CD4+ Th cell responses during chronic infection and immunotherapy.