Spatial regulation of CD8+ T cells at the HLA-E-NKG2A axis drives HIV persistence in lymph node B cell follicles
Andrea Olga Papadopoulos, Leonard Mvaya, Trevor Khaba, Namani Ngema, Werner Smidt, Sibongiseni Msipa, Bongiwe Mahlobo, Thandekile Ngubane, Krista L. Dong, Ismail Jajbhay, Johan Pansegrouw, Kondwani Jambo, Zaza M. Ndhlovu
Abstract
B cell follicles (BCFs) in the lymph node are a major sanctuary for HIV reservoirs. Immune regulatory mechanisms hindering cytolytic CD8 + responses at these sites are poorly characterized, likely enabling HIV persistence. Spatial transcriptomics and high-dimensional histocytometry were used to define CD8 + T cell function and immune regulation in lymph node (LN) follicles of people living with HIV (PLWH), at various stages of antiretroviral therapy (ART) treatment. Histocytometry demonstrated that CD8 + T cells infiltrating BCFs mostly lacked granzyme B expression, coinciding with reduced chromatin access at cytolytic gene loci in dissociated lymph node cells. Spatial transcriptomics confirmed the immune regulatory microenvironment of HIV-infected BCFs, particularly exhibiting upregulation of HLA-E. Additional fluorescence-activated cell sorting (FACS) analysis identified a subset of LN CD8 + T cells expressing the NKG2A-interacting partner of HLA-E, with reduced granzyme B expression. These findings suggest that regulation of follicular CD8 + T cells at the HLA-E-NKG2A axis may be a key mechanism for HIV immune evasion.