IL-15 promotes activation and expansion of CD8+ T cells in HIV-1 infection.
In HIV-1-infected patients, increased numbers of circulating CD8+ T cells are linked to increased risk of morbidity and mortality. Here, we identified a bystander mechanism that promotes CD8 T cell activation and expansion in untreated HIV-1-infected patients. Compared with healthy controls, untreated HIV-1-infected patients have an increased population of proliferating, granzyme B+, CD8+ T cells in circulation. Vβ expression and deep sequencing of CDR3 revealed that in untreated HIV-1 infection, cycling memory CD8 T cells possess a broad T cell repertoire that reflects the repertoire of the resting population. This suggests that cycling is driven by bystander activation, rather than specific antigen exposure. Treatment of peripheral blood mononuclear cells with IL-15 induced a cycling, granzyme B+ phenotype in CD8+ T cells. Moreover, elevated IL-15 expression in the lymph nodes of untreated HIV-1-infected patients correlated with circulating CD8+ T cell counts and was normalized in these patients following antiretroviral therapy. Together, these results suggest that IL-15 drives bystander activation of CD8+ T cells, which predicts disease progression in untreated HIV-1-infected patients and suggests that elevated IL-15 may also drive CD8+ T cell expansion that is linked to increased morbidity and mortality in treated patients.
Souheil-Antoine
SA
Younes
Michael L
ML
Freeman
Joseph C
JC
Mudd
Carey L
CL
Shive
Arnold
A
Reynaldi
Soumya
S
Panigrahi
Jacob D
JD
Estes
Claire
C
Deleage
Carissa
C
Lucero
Jodi
J
Anderson
Timothy W
TW
Schacker
Miles P
MP
Davenport
Joseph M
JM
McCune
Peter W
PW
Hunt
Sulggi A
SA
Lee
Sergio
S
Serrano-Villar
Robert L
RL
Debernardo
Jeffrey M
JM
Jacobson
David H
DH
Canaday
Rafick-Pierre
RP
Sekaly
Benigno
B
Rodriguez
Scott F
SF
Sieg
Michael M
MM
Lederman
D000328:Adult; D000368:Aged; D000818:Animals; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D001706:Biopsy; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology*; D016022:Case-Control Studies; D049109:Cell Proliferation; D005260:Female; D053804:Granzymes / Q000378:metabolism; D015658:HIV Infections / Q000097:blood*; D015497:HIV-1; D006239:Haplotypes; D006801:Humans; D019409:Interleukin-15 / Q000378:metabolism*; D019394:Ki-67 Antigen / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008198:Lymph Nodes / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008875:Middle Aged; D010641:Phenotype; D054400:Receptors, CCR7 / Q000378:metabolism
D044966:Anti-Retroviral Agents; C515371:Ccr7 protein, mouse; C569274:IL15 protein, human; D019409:Interleukin-15; D019394:Ki-67 Antigen; D054400:Receptors, CCR7; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse; D053804:Granzymes