GITR activation ex vivo impairs CD8 T cell function in people with HIV on antiretroviral therapy

Céline Gubser; Rachel D Pascoe; Judy Chang; Chris Chiu; Ajantha Solomon; Rosalyn Cao; Thomas A Rasmussen; Sharon R Lewin

doi:10.1016/j.isci.2023.108165

GITR activation ex vivo impairs CD8 T cell function in people with HIV on antiretroviral therapy

iScience. 2023 Nov 2;26(11):108165. doi: 10.1016/j.isci.2023.108165. eCollection 2023 Nov 17.

Authors

Céline Gubser¹, Rachel D Pascoe², Judy Chang¹, Chris Chiu¹, Ajantha Solomon¹, Rosalyn Cao¹, Thomas A Rasmussen^{1

3}, Sharon R Lewin^{1

4

5}

Affiliations

¹ Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
² Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
³ Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
⁴ Victorian Infectious Diseases Service, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
⁵ Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, VIC, Australia.

Abstract

Glucocorticoid-induced tumor necrosis factor related protein (GITR) is a co-stimulatory immune checkpoint molecule constitutively expressed on regulatory T cells (T_regs) and on activated T conventional cells (T_conv). In blood collected from PWH on suppressive ART, GITR expression was reduced in multiple activated CD4 and CD8 T cell subsets but was increased in Tregs. HIV specific CD8 T cells expressed higher levels of GITR and programmed cell death protein 1 (PD-1) compared to total CD8 T cells. Following stimulation with HIV peptides and GITR-ligand (L), we demonstrated a significant decrease in killing by HIV specific CD8 T cells and an increased exhausted profile. T cell receptor co-stimulation with GITR-L abrogated T_reg suppression and induced expansion of CD4 T_conv. We conclude that GITR activation is an additional factor contributing to an impaired HIV immune response in PWH on ART and that GITR agonist antibodies should not be pursued for HIV cure strategies.

Keywords: Cell biology; Immunology.

Grants and funding

UM1 AI126611/AI/NIAID NIH HHS/United States