Biology subjects

Mukhiya, R.

Publications and source records attributed to Mukhiya, R..

2 recordsLinked to original sources

bioRxiv2025

CCR7 Expression Distinguishes Functionally Distinct pTfh1 Subsets with Roles in Malaria-Specific Immunity

Antibodies induced by infection or vaccination are essential mediators of protection. Induction of these protective responses is mediated by T-follicular CD4 T (Tfh) cells, and targeting these cells may be a strategy to boost antibody mediate protection. In humans, Tfh cells are analysed based on expression of CXCR3 and CCR6, with different subsets of Tfh (Tfh1, Tfh2, Tfh17) associated with antibody induction in a context-dependent manner. Here we dissected Tfh cells heterogeneity in healthy donors and individuals during controlled human malaria infection using scRNAseq. We identified two distinct Tfh1-like subsets with functional relevance, defined based on CCR7 expression. CCR7neg Tfh1 cells express markers of cytotoxicity, while CCR7pos Tfh1 cells produce reduced inflammatory cytokines and similar IL-21 resulting in unique cytokine milieu. In controlled human malaria infection, both CCR7pos and CCR7neg Tfh1, along with Tfh2 cells, clonally expanded and were transcriptionally and phenotypically activated. However, only CCR7pos Tfh1 and Tfh2 cells associated with antibody development, suggesting a role for both these Tfh subsets in promoting humoral immunity to malaria. Data identify specific protective Tfh subsets that can be targeted to improve antibody mediated protection to malaria induced, and provide a frame work to dissect the role of Tfh subsets in other disease contexts.

immunology↗

bioRxiv2024

Latent cytomegalovirus is associated with reduced functional antibody induction following Plasmodium falciparum infection

Human immune responses to infection and vaccination are heterogenous, driven by multiple factors including genetics, environmental exposures and personal infection histories. For malaria caused by Plasmodium falciparum parasites, host factors that impact on humoral immunity are poorly understood. We investigated the role of latent cytomegalovirus (CMV) on the host immune response to malaria using blood stage P. falciparum Controlled Human Malaria Infection (CHMI) and in a MSP1 vaccine Phase 1a clinical trial. CMV seropositivity was associated with reduced induction of parasite specific antibodies following malaria infection and vaccination. During infection, reduced antibody induction was associated with modifications to the T -follicular helper (Tfh) cell compartment. CMV seropositivity was associated with a skew towards Tfh1 cell subsets before and after malaria infection, and reduced activation of Tfh2 cells. Protective Tfh2 cell activation was only associated with antibody development in CMV seronegative individuals, and a higher proportion of Tfh1 cells was associated with lower antibody development in CMV seropositive individuals. During MSP1 vaccination, reduced antibody induction in CMV seropositive individuals was associated with CD4 T cell expression of terminal differentiation marker CD57. These findings are particularly relevant for malaria endemic regions where CMV infection is acquired early in life and may modify immunity to malaria gained during infection or vaccination.

immunology↗