Optimal mRNA vaccine-induced CD4⁺ T cell responses require expression of vaccine antigen within hematopoietic cells

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B907
Abstract ID: 6024

Presenting Author:
Julia E Rood , Fellow Physician at Children's Hosp. of Philadelphia

Abstract:

mRNA vaccines elicit robust CD4⁺ T cell responses, but the sources of vaccine antigen responsible for effective T cell priming are unknown. Based on the predominant role of endogenous – rather than exogenous – antigen processing in driving CD4⁺ T cell responses to influenza virus, we hypothesized that endogenous expression of mRNA vaccine antigen within antigen presenting cells is similarly necessary for CD4⁺ T cell priming by mRNA vaccines. Using a series of mRNA vaccines that encode influenza viral proteins and utilize microRNA targeting to generate differential antigen expression in hematopoietic and muscle cells, we examined the relative contribution of exogenous and endogenous antigen presentation to vaccine-specific immune responses. Mice immunized with a hematopoietic-depleted mRNA vaccine demonstrated significantly lower frequencies of IFNg+ antigen-specific CD4⁺ T cells than mice receiving control vaccine, suggesting a crucial role for endogenous antigen presentation. In contrast, immunization with a muscle-depleted vaccine resulted in only a modest reduction in antigen-specific CD4⁺ T cells. Frequencies of T follicular helper cells and antigen-specific antibodies elicited by hematopoietic-depleted vaccine were also lower compared to control vaccine. These findings suggest that endogenous antigen presentation may impact adaptive immune responses to mRNA vaccines more broadly and may inform the development of future vaccines.