Sustained CD28 costimulation is required for self-renewal and differentiation of TCF-1 ⁺ PD-1 ⁺ CD8 T cells

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-1 neg 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.

ER-associated degradation adapter Sel1L is required for CD8+ T cell function and memory formation following acute viral infection

“…It is well established that mitochondrial dynamics are critical for oxidative metabolism. 73 , 74 , 111 , 112 Our data show that Sel1L loss alters mitochondrial morphology, leading to an increase in smaller (i.e., more fissed) mitochondria and increased MERCS formation. Multiple lines of evidence link chronic ER stress to mitochondrial fission and increased mitochondrial-ER contacts.…”

The cholera toxin B subunit induces trained immunity in dendritic cells and promotes CD8 T cell antitumor immunity

“…Training on DCs impacted the functional shape of CD8 T cells infiltrating melanoma tumors, which displayed the expression of Ki67 and Granzyme B, associated with a higher expression of CD44, suggesting that these cells acquired a memory phenotype. Recent reports have suggested that the CD28/CD86 axis in a tumor context is necessary to prevent final CD8 T cell exhaustion and its accumulation ( 79 ).. Moreover, this axis rewires the exhaustion trajectory in CD8 T cells, leading to a more central memory phenotype rather than an exhausted phenotype ( 80 ).…”

Transient PU.1 low fetal progenitors generate lymphoid progeny that contribute to adult immunity

“…However, the decline in the number of CD8 + T cells in the LI of middle-aged UREΔ/Δ mice was not as significant as was observed for CD4 + T cells. Whether this occurred because they are stem-like CD8 T cells that are maintained because of persistent antigen exposure ( Lin et al, 2016 ; Gill et al, 2023 ; Humblin et al, 2023 ), which would be encountered in the large bowel, remains to be determined.…”