LAG-3 sustains TOX expression and regulates the CD94/NKG2-Qa-1b axis to govern exhausted CD8 T cell NK receptor expression and cytotoxicity.
Cell
; 187(16): 4336-4354.e19, 2024 Aug 08.
Article
en En
| MEDLINE
| ID: mdl-39121847
ABSTRACT
Exhausted CD8 T (Tex) cells in chronic viral infection and cancer have sustained co-expression of inhibitory receptors (IRs). Tex cells can be reinvigorated by blocking IRs, such as PD-1, but synergistic reinvigoration and enhanced disease control can be achieved by co-targeting multiple IRs including PD-1 and LAG-3. To dissect the molecular changes intrinsic when these IR pathways are disrupted, we investigated the impact of loss of PD-1 and/or LAG-3 on Tex cells during chronic infection. These analyses revealed distinct roles of PD-1 and LAG-3 in regulating Tex cell proliferation and effector functions, respectively. Moreover, these studies identified an essential role for LAG-3 in sustaining TOX and Tex cell durability as well as a LAG-3-dependent circuit that generated a CD94/NKG2+ subset of Tex cells with enhanced cytotoxicity mediated by recognition of the stress ligand Qa-1b, with similar observations in humans. These analyses disentangle the non-redundant mechanisms of PD-1 and LAG-3 and their synergy in regulating Tex cells.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Antígenos de Histocompatibilidad Clase I
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Antígenos CD
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Linfocitos T CD8-positivos
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Subfamília D de Receptores Similares a Lectina de las Células NK
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Receptor de Muerte Celular Programada 1
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Proteína del Gen 3 de Activación de Linfocitos
Límite:
Animals
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Humans
Idioma:
En
Revista:
Cell
Año:
2024
Tipo del documento:
Article