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- Title
Sustained CD28 costimulation is required for self-renewal and differentiation of TCF-1<sup>+</sup> PD-1<sup>+</sup> CD8 T cells.
- Authors
Humblin, Etienne; Korpas, Isabel; Lu, Jiahua; Filipescu, Dan; van der Heide, Verena; Goldstein, Simon; Vaidya, Abishek; Soares-Schanoski, Alessandra; Casati, Beatrice; Selvan, Myvizhi E.; Gümüş, Zeynep H.; Wieland, Andreas; Corrado, Mauro; Cohen-Gould, Leona; Bernstein, Emily; Homann, Dirk; Chipuk, Jerry; Kamphorst, Alice O.
- Abstract
During persistent antigen stimulation, such as in chronic infections and cancer, CD8 T cells differentiate into a hypofunctional programmed death protein 1–positive (PD-1+) exhausted state. Exhausted CD8 T cell responses are maintained by precursors (Tpex) that express the transcription factor T cell factor 1 (TCF-1) and high levels of the costimulatory molecule CD28. Here, we demonstrate that sustained CD28 costimulation is required for maintenance of antiviral T cells during chronic infection. Low-level CD28 engagement preserved mitochondrial fitness and self-renewal of Tpex, whereas stronger CD28 signaling enhanced glycolysis and promoted Tpex differentiation into TCF-1neg exhausted CD8 T cells (Tex). Furthermore, enhanced differentiation by CD28 engagement did not reduce the Tpex pool. Together, these findings demonstrate that continuous CD28 engagement is needed to sustain PD-1+ CD8 T cells and suggest that increasing CD28 signaling promotes Tpex differentiation into more functional effector-like Tex, possibly without compromising long-term responses. Editor's summary: Stem-like CD8 T cells develop during periods of persistent antigen exposure. During chronic infection and cancer, therapies can stimulate differentiation of antigen-specific stem-like CD8 T cells into cells with effector function; yet factors controlling the integrity of the stem-like T cell pool were unknown. Studying chronic viral infection in mice, Humblin et al. found that the costimulatory molecule CD28 regulated metabolism of stem-like CD8 T cells expressing the inhibitory receptor PD-1 to promote self-renewal and differentiation. In companion work, Gill et al. found that anti–PD-1 blockade, while promoting effector cell differentiation, likewise stimulated the self-renewal of these stem-like T cells, maintaining the size and functionality of the progenitor pool. Thus, immune checkpoint therapies may rejuvenate immune responses without diminishing the durability of the stem-like T cells that respond to treatment. —Sarah H. Ross
- Publication
Science Immunology, 2023, Vol 8, Issue 86, p1
- ISSN
2470-9468
- Publication type
Article
- DOI
10.1126/sciimmunol.adg0878