Structural basis of the TCR-pHLA complex provides insights into the unconventional recognition of CDR3ß in TCR cross-reactivity and alloreactivity.

Evidence shows that some class I human leucocyte antigen (HLA) alleles are related to durable HIV controls. The T18A TCR, which has the alloreactivity between HLA-B∗42:01 and HLA-B∗81:01 and the cross-reactivity with different antigen mutants, can sustain long-term HIV controls. Here the structural basis of the T18A TCR binding to the immunodominant HIV epitope TL9 (TPQDLNTML180-188) presented by HLA-B∗42:01 was determined and compared to T18A TCR binding to the TL9 presented by the allo-HLA-B∗81:01. For differences between HLA-B∗42:01 and HLA-B∗81:01, the CDR1α and CDR3α loops adopt a small rearrangement to accommodate them. For different conformations of the TL9 presented by different HLA alleles, not like the conventional recognition of CDR3s to interact with peptide antigens, CDR3ß of the T18A TCR shifts to avoid the peptide antigen but intensively recognizes the HLA only, which is different with other conventional TCR structures. Featured sequence pairs of CDR3ß and HLA might account for this and were additionally found in multiple other diseases indicating the popularity of the unconventional recognition pattern which would give insights into the control of diseases with epitope mutating such as HIV.

Taming metabolic competition via glycolysis inhibition for safe and potent tumor immunotherapy.

Metabolic competition between tumors and T cells is fierce in the tumor microenvironment (TME). Tumors usually exhaust glucose and accumulate lactic acid in TME. Nutrient deprivation and lactic acid accumulation in TME blunt T cell functions and antitumor immune responses. Here, we reported that glycolysis-related genes were upregulated in melanoma patients with weak immune responses and T cell poorly infiltrated tumors of BRCA and COAD patients. Dimethyl fumarate (DMF), a GAPDH inhibitor, which is FDA proved to treat autoimmune diseases was identified to promote oxidative pentose phosphate pathway through glucose-6-phosphate dehydrogenase (G6PD) but to suppress aerobic glycolysis and oxidative phosphorylation in tumor cells. Additionally, DMF normalized metabolic competition between tumors and T cells, thus potentiate antitumor responses of tumor infiltrating CD8+ T lymphocytes (TILs). Moreover, DMF optimized the efficiency of immune checkpoint therapy and interleukin-2 (IL-2) therapy while eliminating severe toxicity induced by IL-2 therapy. This study indicates a novel clinically feasible therapy strategy aiming shared metabolic pathway of tumors and T cells for effective and less toxic tumor immunotherapy.