Simian Immunodeficiency Virus-Producing Cells in Follicles Are Partially Suppressed by CD8⁺CellsIn Vivo

Abstract

Human immunodeficiency virus (HIV)-and simian immunodeficiency virus (SIV)-specific CD8؉ T cells are typically largely excluded from lymphoid B cell follicles, where HIV-and SIV-producing cells are most highly concentrated, indicating that B cell follicles are somewhat of an immunoprivileged site. To gain insights into virus-specific follicular CD8؉ T cells, we determined the location and phenotype of follicular SIV-specific CD8 ؉ T cells in situ, the local relationship of these cells to Foxp3 ؉ cells, and the effects of CD8 depletion on levels of follicular SIV-producing cells in chronically SIV-infected rhesus macaques. We found that follicular SIV-specific CD8 ؉ T cells were able to migrate throughout follicular areas, including germinal centers. Many expressed PD-1, indicating that they may have been exhausted. A small subset was in direct contact with and likely inhibited by Foxp3؉ cells, and a few were themselves Foxp3 ؉ . In addition, subsets of follicular SIV-specific CD8 ؉ T cells expressed low to medium levels of perforin, and subsets were activated and proliferating. Importantly, after CD8 depletion, the number of SIVproducing cells increased in B cell follicles and extrafollicular areas, suggesting that follicular and extrafollicular CD8؉ T cells have a suppressive effect on SIV replication. Taken together, these results suggest that during chronic SIV infection, despite high levels of exhaustion and likely inhibition by

Immune checkpoint blockade in infectious diseases

“…PD-1 is also highly expressed by cytotoxic CD8 + T cells that migrate into lymphoid follicles; these follicular cytotoxic CD8+ T cells express high levels of CXCR5 and PD-1 but low levels of other immune checkpoint proteins, such as TIM3 45 . There is an inverse association between the frequency of cytotoxic CD8 + T cells and HIV-infected cells in lymphoid follicles and a similar inverse relationship has been recently observed in untreated SIV infection 45–47 . Finally, ex vivo blockade with anti-PD-1 or anti-PD-L1 resulted in enhanced HIV-specific CD8 + T cell function and killing of infected target cells 36,43,44 (Table 2), as described for cancer antigens.…”

From dendritic cells to B cells dysfunctions during HIV‐1 infection: T follicular helper cells at the crossroads

“…HIV‐specific CXCR5 + CD8 + T‐cell numbers were inversely correlated with viral load in HIV‐infected patients . Similar data have been reported in SIV‐infected animals . Hence, understanding how to direct the differentiation and function of Tfc cells might help in the design of new strategies for eliminating HIV reservoirs.…”

CD4 T Follicular Helper and Regulatory Cell Dynamics and Function in HIV Infection

“…Most SIV-specific CTL lack a follicular homing phenotype (CXCR5+CCR7−), which may explain their failure to home to sites of virus replication in B cell follicles (39). Depletion of CD8 cells from SIV-infected macaques leads to increases in virus replication primarily in the extrafollicular zone, further supporting the notion that CTL are primarily active in the extrafollicular compartment and exert little antiviral activity within the follicle (45). Thus, T FH are naturally highly susceptible to HIV, and their location within the immune privileged B cell follicle adjacent to FDC-bound virions further promotes high levels of HIV infection and replication.…”