Association between circulating exhausted CD4+ T cells with poor meningococcal C conjugate vaccine antibody response in HIV-infected children and adolescents

Abstract

To investigate the expression levels of surface markers of activation (CD38 and HLA-DR), inhibition (PD-1, TIGIT and CD57) and co-stimulation (CD28 and CD127) on CD4 + T cells of children/adolescents with vertical HIV infection (HI patients) and HIV-uninfected (HU) controls vaccinated with the meningococcal C conjugate vaccine (MCC). METHODS: HI patients (n=12), aged 8-17 years, were immunized with two MCC injections, while HU controls (n=9), aged 5.3-10.7 years, received a single MCC dose (as per national recommendation at the time of this study, a single MCC vaccine dose should be given for healthy children and youth aged 1-18 years). The HI patients were categorized according to the combined antiretroviral therapy (cART) treatment. Blood samples were obtained before vaccination, after priming, and after the administration of a booster dose of vaccine to determine the serum bactericidal antibody (SBA) titers and the expression levels of surface markers on CD4 + T cells by flow cytometry. The levels of serum cytokines, IL-4 and CXCL-13 were also measured using Luminex kits. RESULTS: The co-expression of the TIGIT-HLA-DR-CD38 molecules increased in the CD4 + T cells of HI patients/ no-cART who also showed a lower frequency of CD127 + CD28 + CD4 + T cells than HI patients/cART and HU group subjects. There were significant negative correlations between the frequency of exhausted CD4 + T cells and the SBA response. IL-4 levels were higher in HI patients/cART and positively correlated with SBA titers but negatively associated with the expression of exhaustion markers. Moreover, the CXCL-13 levels were positively correlated with the exhausted CD4+ T cells. CONCLUSION: The results of our study suggest that the co-expression of exhaustion markers and/or loss of co-stimulatory molecules influence the SBA response in HI patients.

Expression of TIGIT, PD-1 and HLA-DR/CD38 markers on CD8-T cells of children and adolescents infected with HIV and uninfected controls

“…We have recently described a clear association between circulating exhausted CD4 + T cells with poor meningococcal C conjugate vaccine antibody response in the same HI cohort of this study 11 . Our interest in this investigation was to analyze the expression of the same activation/exhaustion markers (TIGIT, PD-1, HLA-DR, and CD38) studied before, to characterize CD8 T cells of HI/cART and HI/no cART patients, when compared to HU individuals.…”

“…In HI/cART and HI/no cART groups, 67% and 40% of participants were male, respectively. At baseline, CD4 count was 958 (523–1,267) and 525 (479–628) cells/µL, nadir CD4 was 13% (1–34) and 22% (16–26), and HIV RNA was <50 and 17,492 (301–65,701) copies/mL for HI/cART and HI/no-cART group, respectively, as previously described 11 . The median length of cART was 5.9 years (5.4–11.9).…”

“…These results suggest that the accumulation of exhausted/inhibitory markers on T lymphocytes may be an important fact associated with the dysfunctionality of these cells. Accordingly, we previously reported the existence of a negative association of exhausted CD4 T cells with blood levels of IL-4, contrasting with a negative link with CXCL-13 levels 11 .…”

“…We took advantage of our previous study 11 and analyzed the association between CD8 + T cells and CD4 + T cells co-expressing CD38/DR/TIGIT or CD38/DR/PD-1. A significant association was observed between CD4 and CD8 T cells co-expressing CD38/DR/TIGIT for T0 (r = 0.86, p <0.01, data not shown) and T1 (r = 0.78, p < 0.01, Figure 3C ).…”

“…In our cohort, we observed that children/adolescents not receiving cART showed a higher frequency of CD8 T cells expressing exhaustion/activation markers as TIGIT/ PD-1/CD38/DR, when compared to treated patients and uninfected controls. The median length of cART was 5.9 years and 5 out of 6 patients on cART were in CDC category C 11 since the Brazilian guidelines for cART initiation in children and adolescents at the time of the onset of this study, in 2011, were restricted to patients in the CDC clinical categories B or C or patients with at least one of the following parameters: CD4 count less than 350 cells/mL, CD4 percentage less than 15%, or viral load >100,000 copies/mL 15 . Therefore, these data suggest that the early onset of cART probably would have contributed to a greater immune reconstitution of those pediatric patients, as described in the literature 16 .…”