CD160 and PD-1 co-expression on HIV-specific CD8 T cells defines a subset with advanced dysfunction.
Chronic viral infections lead to persistent CD8 T cell activation and functional exhaustion. Expression of programmed cell death-1 (PD-1) has been associated to CD8 T cell dysfunction in HIV infection. Herein we report that another negative regulator of T cell activation, CD160, was also upregulated on HIV-specific CD8 T lymphocytes mostly during the chronic phase of infection. CD8 T cells that expressed CD160 or PD-1 were still functional whereas co-expression of CD160 and PD-1 on CD8 T cells defined a novel subset with all the characteristics of functionally exhausted T cells. Blocking the interaction of CD160 with HVEM, its natural ligand, increased HIV-specific CD8 T cell proliferation and cytokine production. Transcriptional profiling showed that CD160(-)PD-1(+)CD8 T cells encompassed a subset of CD8(+) T cells with activated transcriptional programs, while CD160(+)PD-1(+) T cells encompassed primarily CD8(+) T cells with an exhausted phenotype. The transcriptional profile of CD160(+)PD-1(+) T cells showed the downregulation of the NFκB transcriptional node and the upregulation of several inhibitors of T cell survival and function. Overall, we show that CD160 and PD-1 expressing subsets allow differentiating between activated and exhausted CD8 T cells further reinforcing the notion that restoration of function will require multipronged approaches that target several negative regulators.
Caprion/ImmuneCarta Services, Montreal, Quebec, Canada.
Yoav
Y
Peretz
Zhong
Z
He
Yu
Y
Shi
Bader
B
Yassine-Diab
Jean-Philippe
JP
Goulet
Rebeka
R
Bordi
Ali
A
Filali-Mouhim
Jean-Baptiste
JB
Loubert
Mohamed
M
El-Far
Franck P
FP
Dupuy
Mohamed Rachid
MR
Boulassel
Cécile
C
Tremblay
Jean-Pierre
JP
Routy
Nicole
N
Bernard
Robert
R
Balderas
Elias K
EK
Haddad
Rafick-Pierre
RP
Sékaly
D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology*; D005260:Female; D058851:GPI-Linked Proteins / Q000096:biosynthesis / Q000276:immunology; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis / Q000276:immunology*; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology*
D015703:Antigens, CD; C114505:CD160 protein, human; D016207:Cytokines; D058851:GPI-Linked Proteins; D016328:NF-kappa B; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic