Functional Implications of Tfh Cell Heterogeneity after Infection

SUMMARY. Vaccination is one of the most important public health achievements in history. However, we are still unable to induce protective immunity against important human pathogens, such as influenza. Thus, infectious diseases remain a major cause of disability and death. An essential component of a "successful" vaccine is the ability to generate long-lived plasma cells (LLPCs) AND memory B cells, which produce protective antibodies (Ab) and provide long-term prophylactic immunity. Importantly, the development of LLPCs and memory B cells occurs in the germinal center (GC). Thus, it is essential to understand the mechanisms that control the GC reaction. However, despite significant advances in the field, our understanding of the mechanisms that control the GC responses is still limited. One of the critical gaps in our knowledge is how "GC fate decisions" are regulated, particularly how GC B cells "choose" between staying in the GC to differentiate into highly mutated LLPCs or becoming memory B cells and leave the GCs. The lack of precise knowledge of the mechanisms that fine-tune the output of the GC is one of the main limitations when designing new vaccination strategies to overcome individual pathogen adaptions. In this regard, previous studies demonstrate that preexisting influenza-specific memory B cells in the lungs provide critical protection after reinfection. However, the factors that control the generation of lung memory B cell responses remain elusive. We believe this knowledge will be essential for designing more efficient vaccination strategies against respiratory viruses, such as influenza or SARS-CoV2. Importantly, CD4+ T follicular helper (Tfh) cells play a fundamental role in promoting GC B cell responses. In fact, in the absence of Tfh cells, GC responses and Ab-mediated protection are impaired. Thus, it is generally believed that an "enhanced" Tfh cell response after vaccination will significantly improve the efficacy of vaccines. Unfortunately, we still do not know what functional properties define a "high-quality" Tfh cell response. Our preliminary data demonstrate that, as the immune response progresses, the influenza-specific Tfh cell response "evolves." As a consequence, different subsets of Tfh cells are present at different times after influenza infection. Based on our data, we hypothesize that GC B cells interacting with different "flavors" of Tfh cells at different times after infection receive qualitatively different signals, which temporarily fine-tunes the output of the GC and the generation of lung memory B cells. The long-term goals of this application are 1) To determine the role played by distinct subsets of Tfh cells in controlling the memory/LLPC differentiation balance. 2) To define the mechanisms that regulate the generation of "high quality" Tfh cells with the ability to promote enhanced B cell-mediated protection against respiratory viruses. 3) To determine the molecular and transcriptional mechanisms that control the generation of pulmonary memory B cells and the memory/LLPC differentiation balance in the GCs. We believe this knowledge will be essential for designing new vaccination strategies tailored against respiratory viruses.