Contribution Of Non-Classical Antigen Presentation To Cd4+ T Cells During Orthopoxvirus Infection

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Doctor of Philosophy (PhD)
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antigen processing
CD4+ T cell
Major Histocompatibility Complex II
Allergy and Immunology
Immunology and Infectious Disease
Medical Immunology
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Forsyth, Katherine Shona

CD4+ T cells play critical roles in host defense during viral infection, yet questions remain regarding the mechanisms for activation of these cells. The critical initiating signal for CD4+ T cell activation is a productive interaction between the T cell receptor and an antigenic peptide in complex with an MHCII molecule on an antigen presenting cell. However, the primary means by which these peptides are generated and loaded onto MHCII molecules is debated. Historically antigen presenting cells have been thought to utilize the classical pathway of exogenous presentation, whereby extracellular antigenic material is endocytosed and catabolized to peptides within the endocytic network. However, recent work has demonstrated that during influenza infection the primary method by which peptides are presented on MHCII is through direct endogenous processing by an infected antigen presenting cell; this method of processing utilizes a network of subcellular mediators beyond the endocytic compartment. Whether direct endogenous peptide processing plays a substantial role in MHCII-mediated CD4+ T cell activation during other infections has not been characterized. Here we examined the mechanisms of MHCII processing used during ectromelia infection, the causative agent of mousepox and a close relative of smallpox and monkeypox. First, we determined that whole poxvirions are refractory to processing via the classical exogenous pathway and that use of this pathway alone does not lead to a protective CD4+ T cell response. In the course of this work we also identified many novel ectromelia-derived peptides that could stimulate CD4+ T cell activation and be used to further probe the cellular requirements for MHCII processing of ectromelia. Second, we demonstrated that ectromelia encodes a protein that specifically targets direct endogenous MHCII presentation and interferes with CD4+ T cell synapse formation, a critical event in productive T cell receptor interactions. This inhibitory mechanism appears to skew presentation activity towards uninfected cells that acquire material from infected cells in a process termed antigen transfer. Together, these studies reveal further mechanistic complexities in generating a protective anti-viral CD4+ T cell response.

Laurence C. Eisenlohr
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