Principal Investigator

Andrea Sant, Ph.D. University of Rochester work Box 609 601 Elmwood Ave Rochester NY 14642 office: KMRB 3-9645 p (585) 275-9798

Peptide Persistence on Class II Provides a Competitive Advantage to T Cells During Priming and Expansion In Vivo

Peptides that bind with high stability to class II have an advantages in their initial epitope density due to differential DM editing after antigen uptake. They have additional advantages in recruiting late-arriving CD4 T cells in the lymph node. These peptides can also sustain their responses in the presence of competing responses by T cells with different specificities.

Recent findings describing the dynamic interactions of antigen-bearing dendritic cells and T cells suggested to us that peptide off-rates from class II molecules may impact the immune outcome at several levels, after the initial expression at the cell surface. To explore this issue, we evaluated whether CD4 T cell responses were impacted by the ability of class II peptide complexes to persist after export to the cell surface. We also asked whether the presence of ongoing CD4 responses to unrelated peptides influenced the full expansion of CD4 T cells during a primary response to peptide based vaccines. In these studies, antigen processing, and thus the impact of DM editing was bypassed by immunizing animals with synthetic peptides, in adjuvant.

Although peptides with low stability interactions with the presenting class II molecule can recruit CD4 T cells into a response when they are administered alone, they fail to do so when they are administered together with competing peptides. If you improve the ability of a peptide to bind to class II, it can now sustain responses when introduced with competing peptides.

Under these conditions, peptides of differing kinetic stability with class II would be initially loaded onto the priming APC at the same density and we could ask whether differential persistence of peptide:class II complexes influenced the final specificity of the elicited CD4 T cell response. Our results show that peptides with rapid decay rates from class II molecules are able to initially expand CD4 T cells, but fail to sustain T cell activation. Collectively, these results argue that during an immune response, even when antigen processing and DM editing is bypassed, there are other potent regulatory events that drive the selectivity in the T cell repertoire to a restricted set of peptides that possess highly stable interactions with the presenting MHC class II molecules. Collectively these results compel us to consider why the immune system might have evolved to select only stable peptide:class II complexes for the focus of CD4 T cells. One possibility is that persistence of a peptide on the class II molecule provides an advantage for stable CD4 memory generation and maintenance. Although it is known that antigen persistence is not essential to generate memory cells, it is possible that continued opportunities to engage the CD4 T cells agonist ligand provides some advantage in the quantity or quality of memory T cells. Also, engagement of CD4 T cells, particularly follicular helper T cells with antigen-specific B cells in the germinal center may be most efficient for stable peptide:class II complexes.

Peptide persistence controls the development of a productive immune response at several levels.

Recent studies suggest that follicular helper cells are sequestered with antigen-bearing APC for extended periods of time in the germinal center of lymph nodes during a T cell dependent antibody response. These prolonged interactions between CD4 T cells with antigen-bearing B cells may be essential for the formation of a production germinal center reaction. CD4 T cells specific for unstable peptide:class II complexes might not be useful for providing this help for immunoglobulin isotype switching and affinity maturation. Finally, delivery of effector function during pathogen-specific responses may be more efficient for CD4 T cells if their TcR ligand on the target cells persists at high epitope density after pathogen protein synthesis has diminished, allowing for complete removal of pathogen-bearing cells. Any or all of these activities of CD4 T cells may be most efficiently delivered if the ligand for the TcR persists for extended periods of time on the antigen-bearing APC. If the initial priming of CD4 T cells was regulated by the largely unpredictable process of proteolytic release rather than a stable property of the peptide class II complex, the initial CD4 expansion in the primary response would include those that rapidly decay from the class II molecule. It may be quite counterproductive to initially prime and enrich for CD4 T cells that are specific for low stability peptide:class II ligands because these CD4 T cells may ultimately be less ‘fit’ in effector function activity or providing long term memory responses to pathogens.

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