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• W3201455768 abstract "We have sought to understand the role that epitopespecificity in the CD4 T cell repertoire has on the functionaloutcome of both the CD4 T cell response and ultimately the B cellresponse to influenza infection. Protection against influenzainfection, provided by immune memory elicited from eitherinfection or vaccination, is primarily mediated by neutralizingantibody. The humoral response is in turn dependent on thefollicular helper T cell (Tfh) response for the provision ofcognate T cell help in the germinal center reaction. Accordingly,we envision several scenarios where T cell specificity may beaffecting the immune response, including the selection of which Bcells receive help, and which CD4 T cells become Tfh. To this end,this thesis work has taken a twopronged approach to elucidate theeffects of specificity in shaping the adaptive immune response. First, we employed a strategy of peptide priming to establishmemory CD4 T cells so that we could directly query the effects ofT cell specificity on the primary B cell response to influenzainfection. We discovered that only T cells of matched proteinspecificity were capable of helping antigen-specific B cells.Nucleoprotein-specific CD4 T cell memory was uniquely positionedto provide help to NP-specific B cells, but were unable to boostthe HA-specific B cell response, indicating that T cell help wasboth limiting and selective for the primary B cell response. Theopposite was true of HA specific CD4 cells. This work underscoredthe importance of CD4 T cell memory in shaping novel B cellresponses to infection. To understand the role of specificity inselecting CD4 T cells into a pathway of Tfh differentiation, westudied the repertoire of Tfh and NonTfh cells generated afterinfluenza infection. Surprisingly, we delineated distinct epitopesin two different influenza proteins that were more proficient atdriving a Tfh-biased effector response. For many epitopes, thesepreferences persisted in responses to both protein vaccination,and in the context of heterologous protein vaccination usingconstructs containing influenza epitopes. We were able todemonstrate that T cell specificity was sufficient to drive aparticular differentiation bias towards either Tfh or NonTfhdespite the overlying cytokine and costimulatory milieu providedby infection or vaccination. We have demonstrated theimportance of CD4 T cell specificity both in shaping the effectorrepertoire of responding CD4 T cells, and in selecting thespecificity of the B cell response to infection. This workcontributes to our understanding of how the effector CD4 T cellrepertoire is developed, and how CD4 T cell memory can influencefuture responses to infection or vaccination. The implications forhuman vaccine design are several-fold, including the following.These results delineate a potential approach for optimizing theCD4 T cell effector repertoire for antibody responses, a strategyfor focusing the B cell response to infection by tailoring CD4 T…" @default.
• W3201455768 created "2021-09-27" @default.
• W3201455768 creator A5074802230 @default.
• W3201455768 date "2016-01-01" @default.
• W3201455768 modified "2023-09-27" @default.
• W3201455768 title "The Influence of CD4 T Cell Specificity onDifferentiation of the Repertoire and Shaping the Adaptive ImmuneResponse to Influenza Infection" @default.
• W3201455768 hasPublicationYear "2016" @default.
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