Details

Autor(en) / Beteiligte

• Snell, Laura M.
• MacLeod, Bethany L.
• Law, Jaclyn C.
• Osokine, Ivan
• Elsaesser, Heidi J.
• Hezaveh, Kebria
• Dickson, Russell J.
• Gavin, Marc A.
• Guidos, Cynthia J.
• McGaha, Tracy L.
• Brooks, David G.

Titel

CD8+ T Cell Priming in Established Chronic Viral Infection Preferentially Directs Differentiation of Memory-like Cells for Sustained Immunity

Ist Teil von

• Immunity (Cambridge, Mass.), 2018-10, Vol.49 (4), p.678-694.e5

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Link zum Volltext

Quelle

ScienceDirect

Beschreibungen/Notizen

• CD8+ T cell exhaustion impedes control of chronic viral infection; yet how new T cell responses are mounted during chronic infection is unclear. Unlike T cells primed at the onset of infection that rapidly differentiate into effectors and exhaust, we demonstrate that virus-specific CD8+ T cells primed after establishment of chronic LCMV infection preferentially generate memory-like transcription factor TCF1+ cells that were transcriptionally and proteomically distinct, less exhausted, and more responsive to immunotherapy. Mechanistically, adaptations of antigen-presenting cells and diminished T cell signaling intensity promoted differentiation of the memory-like subset at the expense of rapid effector cell differentiation, which was now highly dependent on IL-21-mediated CD4+ T cell help for its functional generation. Chronic viral infection similarly redirected de novo differentiation of tumor-specific CD8+ T cells, ultimately preventing cancer control. Thus, targeting these T cell stimulatory pathways could enable strategies to control chronic infection, tumors, and enhance immunotherapeutic efficacy. [Display omitted] •CD8+ T cell priming in chronic infection (Tlp) programs TCF1+ differentiation•Tlp are less exhausted and have superior responsiveness to PDL1 blockade•Decreased APC-mediated T cell stimulation primes TCF1+ cell differentiation•Chronic infection redirects tumor-specific CD8+ T cell differentiation How new T cell responses are mounted during chronic infection is unclear. Snell et al. demonstrate that unlike T cells primed at the onset of infection, CD8+ T cells primed after chronic viral infection is established are differentially programmed into less exhausted, TCF1+ memory-like cells that respond better to immunotherapy but diminish immunity to cancers that arise in chronic infection.