6MP1

Crystal structures of the murine class I major histocompatibility complex H-2Db in complex with the mutant TRP1-K8 peptide

Summary for 6MP1

• Entry DOI: 10.2210/pdb6mp1/pdb
• Descriptor: TRP1-K8 peptide, Beta-2-microglobulin,H-2 class I histocompatibility antigen, D-B alpha chain, chimeric construct, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: mhc, immune system
• Biological source: Mus musculus (Mouse); More
• Total number of polymer chains: 1
• Total formula weight: 50461.83

Authors

Clancy-Thompson, E.,Devlin, C.A.,Birnbaum, M.E.,Dougan, S.K. (deposition date: 2018-10-05, release date: 2018-11-07, Last modification date: 2023-10-11)

Primary citation

Clancy-Thompson, E.,Devlin, C.A.,Tyler, P.M.,Servos, M.M.,Ali, L.R.,Ventre, K.S.,Bhuiyan, M.A.,Bruck, P.T.,Birnbaum, M.E.,Dougan, S.K.
Altered Binding of Tumor Antigenic Peptides to MHC Class I Affects CD8+T Cell-Effector Responses.
Cancer Immunol Res, 6:1524-1536, 2018

PubMed Abstract: T-cell priming occurs when a naïve T cell recognizes cognate peptide-MHC complexes on an activated antigen-presenting cell. The circumstances of this initial priming have ramifications on the fate of the newly primed T cell. Newly primed CD8 T cells can embark onto different trajectories, with some becoming short-lived effector cells and others adopting a tissue resident or memory cell fate. To determine whether T-cell priming influences the quality of the effector T-cell response to tumors, we used transnuclear CD8 T cells that recognize the melanoma antigen TRP1 using TRP1 or TRP1 TCRs that differ in both affinity and fine specificity. From a series of altered peptide ligands, we identified a point mutation (K8) in a nonanchor residue that, when analyzed crystallographically and biophysically, destabilized the peptide interaction with the MHC binding groove. , the K8 peptide induced robust proliferation of both TRP1 and TRP1 CD8 T cells but did not induce expression of PD-1. Cytokine production from K8-stimulated TRP1 cells was minimal, whereas cytotoxicity was increased. Upon transfer into B16 tumor-bearing mice, the reference peptide (TRP1-M9)- and K8-stimulated TRP1 cells were equally effective at controlling tumor growth but accomplished this through different mechanisms. TRP1-M9-stimulated cells produced more IFNγ, whereas K8-stimulated cells accumulated to higher numbers and were more cytotoxic. We, therefore, conclude that TCR recognition of weakly binding peptides during priming can skew the effector function of tumor-specific CD8 T cells.

PubMed: 30352798
DOI: 10.1158/2326-6066.CIR-18-0348

Experimental method

X-RAY DIFFRACTION (2.211 Å)