Accumulation of follicular CD8+ T cells in pathogenic SIV infection

Abstract

LN follicles constitute major reservoir sites for HIV/SIV persistence. Cure strategies could benefit from the characterization of CD8+ T cells able to access and eliminate HIV-infected cells from these areas. In this study, we provide a comprehensive analysis of the phenotype, frequency, localization, and functionality of follicular CD8+ T cells (fCD8+) in SIV-infected nonhuman primates. Although disorganization of follicles was a major factor, significant accumulation of fCD8+ cells during chronic SIV infection was also observed in intact follicles, but only in pathogenic SIV infection. In line with this, tissue inflammatory mediators were strongly associated with the accumulation of fCD8+ cells, pointing to tissue inflammation as a major factor in this process. These fCD8+ cells have cytolytic potential and can be redirected to target and kill HIV-infected cells using bispecific antibodies. Altogether, our data support the use of SIV infection to better understand the dynamics of fCD8+ cells and to develop bispecific antibodies as a strategy for virus eradication.

Compromised steady‐state germinal center activity with age in nonhuman primates

“…Therefore, we sought to investigate the steady‐state dynamics of fCD8 T cells with respect to age. Given the lack of a reliable anti‐CD8 clone for FFPE NHP tissue staining, we consider the CD3 hi CD4 lo T‐cell compartment to be highly enriched (the flow cytometry determined % of LN CD3 hi CD4 lo CD8 lo was 1.86 ± 0.542) in CD8 T cells (Figure a) as we recently described (Ferrando‐Martinez et al, ; Watson et al, ). Histocytometry analysis (Figure b) revealed a trend for higher, though not significant, estimated numbers per unit follicular area of CD3 hi CD4 lo T cells within the follicles of old compared to young animals (Figure c and Supporting information Figure a).…”

“…Follicular CD8 (fCD8) T cells, potential regulators of follicular dynamics (Miles et al, ), accumulate during chronic viral infections (Ferrando‐Martinez et al, ) (Mylvaganam et al, ). Therefore, we sought to investigate the steady‐state dynamics of fCD8 T cells with respect to age.…”

“…This shift was associated with an increase of the circulating “effector memory” compartment of both CD4 and CD8 T cells. Given the absence of CCR7 on effector memory circulating T cells (Farber, Yudanin, & Restifo, ), these cells could traffic back to secondary lymphoid organs employing alternative mechanisms like through CXCR3/CXCR3L interactions (Ferrando‐Martinez et al, ; Khan et al, ), a mechanism presumably dependent on local tissue infection and inflammation. The disconnected relative frequencies of memory CD4 and CD8 T cells in circulation and LNs imply that such recruitment of effector cells possibly does not take place in steady‐state NHP LNs.…”

“…Tissue inflammation and immune activation may play a significant role in follicular immunodynamics (Ferrando‐Martinez et al, ). As expected (Pinke et al, ), a higher pro‐inflammatory profile was found in the blood of old animals.…”

“…In contrast, tissue analysis revealed significantly higher numbers of pro‐inflammatory cells (CD163 hi and MPO hi cells) selectively in young follicles, a profile associated with a significant negative association between Tfh and CD163 hi or CD68 hi cells. In addition to their phagocytic function, follicular monocytes/macrophages could secrete cytokines like IL‐1β and chemokines like CXCL‐9, CXCL‐10, and ligands of CXCR3 which is highly expressed in GC T cells (Ferrando‐Martinez et al, ). Therefore, follicular preinflammatory cells could affect GC activity by modulating the function (Ritvo & Klatzmann, ) and/or local trafficking of GC T and B cells (Griffith, Sokol, & Luster, ).…”