Influence of environmental exposures on T follicular helper cell function and implications on immunity: a comparison of Bangladeshi and American children.

T follicular helper (Tfh) cells are crucial for B cell activation and subsequent antibody production. This functionality is influenced by surface markers such as CD40L, a costimulatory factor which promotes B cell activation, and CD57, which is a well-known marker of senescence. This study examined age-specific differences in Tfh cell function in Bangladeshi and American children. At age two, Bangladeshi children displayed impaired CD40L upregulation and significant CD57 downregulation upon stimulation. These patterns, not observed in American children of the same age, suggested an exhaustion-like phenotype potentially driven by environmental factors. Random forest and generalized estimating equations (GEE) modeling was used to analyze predictors of Tfh cell response to stimulation. Days since the last antibiotic treatment, total antibiotic treatments, diarrheal episodes, and malnutrition were identified as variables that significantly impacted the Tfh response to stimuli. To assess Tfh cell ability to promote antibody responses, we correlated Tfh functionality with antibody concentration post-vaccination and in response to infection with Cryptosporidium, an endemic apicomplexan parasite. Increased CD40L expression upon stimulation correlated positively with anti-Poliovirus type 2/3 neutralizing antibody and anti-Cp17 (a Cryptosporidium sporozoite antigen) IgA concentrations. In contrast, increased CD57 expression was significantly correlated with decreased anti-Cp17 IgA. This indicates that an activation-supportive phenotype (CD40L+) may be more effective in promoting immunity than a senescent phenotype (CD57+). Together, these findings suggest that early-life environmental exposures may program Tfh cell functionality, impacting immune response potential in settings with high pathogen exposure.

Importance: T follicular helper (Tfh) cells are upstream mediators that shape the humoral immune response to specific antigens. The generation of an effective memory response to infection is vital to prevent subsequent reinfections. However, in areas with high burdens of exposure to infections, such as the urban community from Bangladesh studied here, children are consistently exposed to inflammatory pathogens. Specific environmental exposures significantly influenced Tfh cell activation and senescence phenotypes. Additionally, Tfh cell responses correlated with antibody concentrations following vaccination or infection, indicating that environmental factors may play a critical role in shaping effective immunity in early childhood.