Julia Merkenschlager: No financial relationships to disclose
Introduction/Rationale: Germinal centers are the sites of antibody affinity maturation and diversification. Both processes are governed by T follicular helper cells (TFH) that recognize and select B cells based on their ability to display cognate peptide-MHCII complexes (p-MHCII). As higher-affinity B cells internalize and present more antigen-derived peptides, the amount of cognate p-MHCII displayed by a B cell is proportional to its affinity toward the immunogen. Although the mechanisms that regulate antibody affinity maturation are well characterized, the regulation of antibody diversification is less understood. We hypothesize that TFH, the cellular conductors of GC B cell selection, may play a role.
Methods: Here, we examined how TCR sensitivity, shapes thresholds for GC B cell selection, using peptide variants that tune T cell activation in vivo and pharmacological modulation of TCR signaling. Through these complementary approaches, we uncover an inverse relationship between T and B cell affinities within the germinal center reaction.
Results: Here we report, that TFH are selected for expression of higher-avidity TCRs, preceding the terminal phase of the response, which is dominated by functionally distinct T follicular regulatory (TFR) . This enhanced sensitivity of TFH TCRs, effectively lowers the threshold for B cell selection, enabling the recruitment and maintenance of a boarder spectrum of B cell affinities.
Conclusion: Together are findings highlight how selection for higher affinity TFH shape the antibody landscape by lowering selection thresholds for B cell selection enabling recruitment and support of more diverse antibody affinities, and provides a new conceptual framework for designing vaccines that calibrate T cell help to steer affinity maturation toward protective antibody responses
