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T follicular helper (TFH) cells play a crucial role in the development of long-lived, high-quality B cell responses after infection and vaccination. However, little is known about how antigen-specific TFH cells clonally evolve in response to complex pathogens and what guides the targeting of different epitopes. Here, we assessed the cell phenotype, clonal dynamics, and T cell receptor (TCR) specificity of human circulating TFH (cTFH) cells during successive malaria immunizations with radiation-attenuated Plasmodium falciparum (Pf) sporozoites. Repeated parasite exposures induced a dynamic, polyclonal cTFH response with high frequency of cells specific to a small number of epitopes in Pf circumsporozoite protein (PfCSP), the primary sporozoite surface protein and well-defined vaccine target. Human leukocyte antigen (HLA) restrictions and differences in TCR generation probability were associated with differences in the epitope targeting frequency and indicated the potential of amino acids 311 to 333 in the Th2R/T* region as a T cell supertope. But most of vaccine-induced anti–amino acid 311 to 333 TCRs, including convergent TCRs with high sequence similarity, failed to tolerate natural polymorphisms in their target peptide sequence, thus demonstrating that the TFH cell response was limited to the vaccine strain. These data suggest that the high parasite diversity in endemic areas will limit boosting of the vaccine-induced TFH cell response by natural infections. Our findings may guide the further design of PfCSP-based malaria vaccines able to induce potent T helper cell responses for broad, long-lasting antibody responses. Malaria vaccine helper: Experimental vaccination with Plasmodium falciparum (Pf) sporozoites (PfSPZ) can induce immune responses that limit the transmission of Pf sporozoites to humans upon the bite of a Pf-infected mosquito. Wahl et al. carried out functional TCR repertoire studies in circulating T follicular helper (cTFH) cells at the single-cell level to understand how this subset contributes to protective immunity. Repeated vaccination with PfSPZ induced a dynamic and polyclonal cTFH response in which a large fraction of cells responded to a small subset of epitopes from the Pf circumsporozoite protein (PfCSP). A T cell supertope was identified as amino acids 311 to 333 in the Th2R/T* region presented by HLA-DR molecules. TCRs recognizing this region were sensitive to parasite sequence variations, providing insight as to why cTFH specific to nonvaccine strains may not support protective responses. [ABSTRACT FROM AUTHOR]

T follicular helper (T FH ) cells play a crucial role in the development of long-lived, high-quality B cell responses after infection and vaccination. However, little is known about how antigen-specific T FH cells clonally evolve in response to complex pathogens and what guides the targeting of different epitopes. Here, we assessed the cell phenotype, clonal dynamics, and T cell receptor (TCR) specificity of human circulating T FH (cT FH ) cells during successive malaria immunizations with radiation-attenuated Plasmodium falciparum ( Pf ) sporozoites. Repeated parasite exposures induced a dynamic, polyclonal cT FH response with high frequency of cells specific to a small number of epitopes in Pf circumsporozoite protein (PfCSP), the primary sporozoite surface protein and well-defined vaccine target. Human leukocyte antigen (HLA) restrictions and differences in TCR generation probability were associated with differences in the epitope targeting frequency and indicated the potential of amino acids 311 to 333 in the Th2R/T* region as a T cell supertope. But most of vaccine-induced anti-amino acid 311 to 333 TCRs, including convergent TCRs with high sequence similarity, failed to tolerate natural polymorphisms in their target peptide sequence, thus demonstrating that the T FH cell response was limited to the vaccine strain. These data suggest that the high parasite diversity in endemic areas will limit boosting of the vaccine-induced T FH cell response by natural infections. Our findings may guide the further design of PfCSP-based malaria vaccines able to induce potent T helper cell responses for broad, long-lasting antibody responses.

Memory B cells (MBCs) epitomize the adaptation of the immune system to the environment. We identify two MBC subsets in peripheral blood, CD27 dull and CD27 bright MBCs, whose frequency changes with age. Heavy chain variable region (VH) usage, somatic mutation frequency replacement-to-silent ratio, and CDR3 property changes, reflecting consecutive selection of highly antigen-specific, low cross-reactive antibody variants, all demonstrate that CD27 dull and CD27 bright MBCs represent sequential MBC developmental stages, and stringent antigen-driven pressure selects CD27 dull into the CD27 bright MBC pool. Dynamics of human MBCs are exploited in pregnancy, when 50% of maternal MBCs are lost and CD27 dull MBCs transit to the more differentiated CD27 bright stage. In the postpartum period, the maternal MBC pool is replenished by the expansion of persistent CD27 dull clones. Thus, the stability and flexibility of human B cell memory is ensured by CD27 dull MBCs that expand and differentiate in response to change., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)