Predominance of weakly cytotoxic, T-betLowEomesNegCD8+T-cells in human gastrointestinal mucosa: implications for HIV infection.
The gastrointestinal mucosa is an important site of HIV acquisition, viral replication, and pathogenesis. Immune cells in mucosal tissues frequently differ in phenotype and function from their non-mucosal counterparts. Although perforin-mediated cytotoxicity as measured in blood is a recognized correlate of HIV immune control, its role in gastrointestinal tissues is unknown. We sought to elucidate the cytotoxic features of rectal mucosal CD8+T-cells in HIV infected and uninfected subjects. Perforin expression and lytic capacity were significantly reduced in rectal CD8+T-cells compared with their blood counterparts, regardless of HIV clinical status; granzyme B (GrzB) was reduced to a lesser extent. Mucosal perforin and GrzB expression were higher in participants not on antiretroviral therapy compared with those on therapy and controls. Reduction in perforin and GrzB was not explained by differences in memory/effector subsets. Expression of T-bet and Eomesodermin was significantly lower in gut CD8+T-cells compared with blood, and in vitro neutralization of TGF-β partially restored perforin expression in gut CD8+T-cells. These findings suggest that rectal CD8+T-cells are primarily non-cytotoxic, and phenotypically shaped by the tissue microenvironment. Further elucidation of rectal immune responses to HIV will inform the development of vaccines and immunotherapies targeted to mucosal tissues.
Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, California, USA.
B E
BE
Kiniry
Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, California, USA.
A
A
Ganesh
Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, California, USA.
J W
JW
Critchfield
Division of Experimental Medicine, San Francisco General Hospital, San Francisco, California, USA.
P W
PW
Hunt
Positive Health Program, Department of Medicine, San Francisco General Hospital, San Francisco, California, USA.
F M
FM
Hecht
Division of Gastroenterology, Department of Medicine, San Francisco General Hospital, San Francisco, California, USA.
M
M
Somsouk
Positive Health Program, Department of Medicine, San Francisco General Hospital, San Francisco, California, USA.
S G
SG
Deeks
Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, California, USA.|Division of Infectious Diseases, Department of Medicine, School of Medicine, University of California, Davis, California, USA.
B L
BL
Shacklett
D016915:AIDS Vaccines / Q000276:immunology*; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D060833:Cellular Microenvironment; D003602:Cytotoxicity, Immunologic; D005260:Female; D053804:Granzymes / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007413:Intestinal Mucosa / Q000276:immunology*; D008297:Male; D054353:Perforin / Q000378:metabolism; D012007:Rectum / Q000378:metabolism* / Q000473:pathology; D020825:T-Box Domain Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000098815:T-bet Transcription Factor
D016915:AIDS Vaccines; D044966:Anti-Retroviral Agents; C491199:EOMES protein, human; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D016212:Transforming Growth Factor beta; D054353:Perforin; D053804:Granzymes