Allogeneic and self peptide–Human Leukocyte Antigen complexes (pHLA complexes)

Allogeneic and self peptide–Human Leukocyte Antigen (HLA) complexes are the fundamental molecular units recognized by the adaptive immune system to distinguish self from non-self. These complexes, expressed on the surface of almost all nucleated host cells, consist of a polymorphic HLA heavy chain, β2-microglobulin (for Class I), and a short peptide fragment derived from cellular or foreign proteins (Murphy et al., Janeway's Immunobiology, 2016). In the context of transplantation, allogeneic pHLA complexes on donor cells are recognized as foreign by the recipient's T cells, leading to graft rejection, while host pHLA complexes can be targeted by donor T cells in graft-versus-host disease (GvHD) (Zeiser & Blazar, N Engl J Med, 2017). In autoimmune diseases, the immune system loses tolerance and inappropriately attacks self-peptide-HLA complexes on healthy tissues (Rock et al., Nat Rev Immunol, 2016). Conversely, in oncology, specific pHLA complexes presenting tumor-associated antigens or neoantigens serve as precise targets for T-cell receptor (TCR) engineered therapies, such as afamitresgene autoleucel, which are designed to selectively eliminate malignant cells (Waldman et al., Nat Rev Immunol, 2020). Therapeutic modulation of these complexes involves either suppressing the immune response in transplantation and autoimmunity or enhancing it to treat cancer and chronic infections.

Other names

Peptide-MHC complexespMHCHLA-peptide complexesAllogeneic HLASelf-antigen HLA complexesMajor Histocompatibility Complex-peptide complexes

Drugs targeting these complexes function by either blocking the interaction between the T-cell receptor (TCR) and the pHLA complex, inhibiting the costimulatory signals required for activation, or utilizing engineered TCRs to specifically recognize and eliminate cells presenting particular peptide-HLA combinations.