High-Frequency, Functional HIV-Specific T-Follicular Helper and Regulatory Cells Are Present Within Germinal Centers in Children but Not Adults

Abstract

Broadly neutralizing antibodies (bnAbs) against HIV-1 are an effective means of preventing transmission. To better understand the mechanisms by which HIV-specific bnAbs naturally develop, we investigated blood and lymphoid tissue in pediatric infection, since potent bnAbs develop with greater frequency in children than adults. As in adults, the frequency of circulating effector T-follicular helper cells (TFH) in HIV infected, treatment naïve children correlates with neutralization breadth. However, major differences between children and adults were also observed both in circulation, and in a small number of tonsil samples. In children, TFH cells are significantly more abundant, both in blood and in lymphoid tissue germinal centers, than in adults. Second, HIV-specific TFH cells are more frequent in pediatric than in adult lymphoid tissue and secrete the signature cytokine IL-21, which HIV-infected adults do not. Third, the enrichment of IL-21-secreting HIV-specific TFH in pediatric lymphoid tissue is accompanied by increased TFH regulation via more abundant regulatory follicular T-cells and HIV-specific CXCR5+ CD8 T-cells compared to adults. The relationship between regulation and neutralization breadth is also observed in the pediatric PBMC samples and correlates with neutralization breadth. Matching neutralization data from lymphoid tissue samples is not available. However, the distinction between infected children and adults in the magnitude, quality and regulation of HIV-specific TFH responses is consistent with the superior ability of children to develop high-frequency, potent bnAbs. These findings suggest the possibility that the optimal timing for next generation vaccine strategies designed to induce high-frequency, potent bnAbs to prevent HIV infection in adults would be in childhood.

Simian-Human Immunodeficiency Virus SHIV.CH505-Infected Infant and Adult Rhesus Macaques Exhibit Similar Env-Specific Antibody Kinetics, despite Distinct T-Follicular Helper and Germinal Center B Cell Landscapes

“…CD4 ϩ Tfh cells are crucial in providing help to B cells in the germinal center (GC) to support antibody maturation (46) and have been shown to be associated with the development of bnAbs during SHIV infection (47), in HIV-infected adults (17), and, more recently, in HIV-infected children (33). A recent study of HIV-1 clade C vertically infected human children and adults demonstrated that frequencies of total Tfh (CXCR5 ϩ PD1 hi ) and HIV-specific (Gag/Env), IL-21-producing GC Tfh cells in oral lymphoid tissue were increased in older children receiving ART (age range, 6 to 10 years); however, it is unknown whether this is true in early life (33). Similarly, in our monkey model, we observed higher frequencies of total lymphoid Tfh and GC B cells in SHIV-infected infants than in adults at 12 wpi ( Fig.…”

“…The quality of these Tfh cell responses may not be optimal early in infection, as we observed that only about 50% of the monkeys in both age groups developed autologous virus neutralization responses by 12 wpi. Furthermore, the differences in Tfh and GC B cells may not be unique to SHIV infection, as the frequencies of lymphoid-resident Tfh cells are also higher in uninfected children than in uninfected adults (33).…”

“…T-follicular helper (Tfh) cells have been reported to be increased in HIV-infected children compared to adults (33). In order to investigate Tfh cell responses during the acute phase of SHIV infection, we evaluated the proportions of CH505-specific and total Table S3 in the supplemental material for both unadjusted P and FDR P values for all comparisons).…”

SHIV.CH505-infected infant and adult rhesus macaques exhibit similar HIV Env-specific antibody kinetics, despite distinct T-follicular helper (Tfh) and germinal center B cell landscapes

“…Frequencies of Tfh cells have been reported to be increased in HIV-infected children compared to adults (26). In order to investigate Tfh cell responses during the early phase of SHIV infection, we evaluated the proportions of CH505-specific (Fig.…”

“…CD4+ T-follicular helper (Tfh) cells are crucial in providing help to B cells in the germinal center (GC) to support antibody maturation (34). A recent study of HIV-1 clade C-infected human children and adults demonstrated that frequencies of total Tfh (CXCR5+ PD1 hi ) and HIV-specific (Gag/Env), IL-21-producing GC-Tfh cells in oral lymphoid tissue were increased in older children receiving ART (age range: 6-10 years), however it is unknown whether this is true in early life (26). In our monkey model, we observed higher frequencies of total lymphoid Tfh cells and GC B cells in SHIV-infected infants compared to adults at 12 wpi (Fig.…”