Simultaneous cognate epitope recognition by bovine CD4 and CD8 T cells is essential for primary expansion of antigen-specific cytotoxic T-cells following ex vivo stimulation with a candidate Mycobacterium avium supsp.

Authors: ABDELLRAZEQ, GABER - Washington State University; Fry, Lindsay; ELNAGGAR, MAHMOUD - Washington State University; Bannantine, John; Schneider, David; CHAMBERLAIN, WILLIAM - Retired Non ARS Employee; MAHMOUD, ASMAA - Alexandria University Of Egypt; PARK, KUN-TAEK - Inje University; HULUBEI, VICTORIA - Washington State University; DAVIS, WILLIAM - Washington State University

Submitted to: Vaccine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/22/2019
Publication Date: 1/3/2020
Citation: Abdellrazeq, G.S., Fry, L.M., Elnaggar, M.M., Bannantine, J.P., Schneider, D.A., Chamberlain, W.M., Mahmoud, A.H.A., Park, K.T., Hulubei, V., Davis, W.C. 2020. Simultaneous cognate epitope recognition by bovine CD4 and CD8 T cells is essential for primary expansion of antigen-specific cytotoxic T-cells following ex vivo stimulation with a candidate Mycobacterium avium supsp. paratubeculosis peptide vaccine. Vaccine. 38(8):2016-2025. https://doi.org/10.1016/j.vaccine.2019.12.052.
DOI: https://doi.org/10.1016/j.vaccine.2019.12.052

Interpretive Summary: The development of a vaccine to protect cattle from Johnes Disease, caused by Mycobacterium avium subsp. paratuberculosis, is of urgent importance to reduce animal losses and improve meat and milk yields from cattle. Protective immunity to this organism requires the development of a functional CD8+ cytotoxic T lymphocyte (CTL) response. In this study, we show that development of a functional CD8+ CTL response to a candidate vaccine antigen, MMP, requires simultaneous recognition of the antigen by both CD4+ and CD8+ T cells (cognate recognition) on antigen presenting cells. This finding will help in vaccine design for Johne's disease and other intracellular infectious diseases, as it provides further evidence that both CD4 T cell targets and CD8 T cell targets should be included in subunit vaccines for these pathogens.

Technical Abstract: Studies in cattle show CD8 cytotoxic T cells (CTL), with the ability to kill intracellular bacteria, develop following stimulation of monocyte-depleted peripheral blood mononuclear cells (mdPBMC) with conventional dendritic cells (cDC) and monocyte-derived DC (MoDC) pulsed with MMP, a membrane protein from Mycobacterium avium subsp. paratuberculosis (Map) encoded by MAP2121c. CTL activity was diminished if CD4 T cells were depleted from mdPBMC before antigen (Ag) presentation by cDC and MoDC, suggesting simultaneous cognate recognition of MMP epitopes presented by MHC I and MHC II molecules might be essential for development of CTL activity. To clarify whether cognate recognition is essential for CTL development, studies were conducted with mdPBMC cultures in the presence of monoclonal antibodies (mAbs) specific for MHC class I and MHC class II molecules. The CTL response of mdPBMC to MMP-pulsed DC was completely blocked in the presence of mAbs to both MHC I and II molecules and also blocked in the presence of mAbs to either MHC I or MHC II. The results demonstrate CD4 T-cell help is essential for development of a primary CTL response to MMP, and indicate that cognate recognition is required for delivery of CD4 T-cell help during priming. Of importance, the findings provide support for the importance of CD4 and CD8 T-cell cognate antigen recognition in eliciting CTL responses to vaccines against intracellular pathogens. The methods described herein can be used to elucidate the intracellular interactions between lymphocytes and DC in humans and cattle.