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Programmed self-assembly of peptide–major histocompatibility complex for antigen-specific immune modulation

Significance T cells play a critical role in the control of diseases, ranging from infection to cancer. However, the activation of antigen-specific T cells against low-affinity antigens, such as tumor self-antigens, remains a challenge. Here, we report a technology for amplifying antigen-specific lymphocyte responses based on orchestrating coordinated signaling events at the level of peptide–major histocompatibility complex (pMHC)–TCR interactions. We engineered a soluble chimeric protein composed of annexin V (ANXA5) linked to pMHC. ANXA5 behaves as an anchor that facilitates stable, repeated cognate pMHC–TCR contacts and TCR cross-linking via programmed self-assembly. pMHC/ANXA5 fusion augments lymphocyte responses by several orders of magnitude and overcomes low-affinity pMHC–TCR interactions. A technology to prime desired populations of T cells in the body—particularly those that possess low avidity against target antigen—would pave the way for the design of new types of vaccination for intractable infectious diseases or cancer. Here, we report such a technology based on positive feedback-driven, programmed self-assembly of peptide–major histocompatibility complex (pMHC) directly on the membrane of cognate T cells. Our design capitalizes on the unique features of the protein annexin V (ANXA5), which—in a concerted and synergistic manner—couples the early onset of TCR signaling by cognate pMHC with a surge in pMHC–TCR affinity, with repeated pMHC encounters, and with widespread TCR cross-linking. In our system, ANXA5 is linked to pMHC and firmly engages the plasma membrane of cognate T cells upon (and only upon) the early onset of TCR signaling. ANXA5, in turn, exerts a mechanical force that stabilizes interactions at the TCR–pMHC interface and facilitates repeated, serial pMHC encounters. Furthermore, ANXA5 quickly arranges into uniform 2D matrices, thereby prompting TCR cross-linking. Fusion of ANXA5 to pMHC augments lymphocyte activation by several orders of magnitude (>1,000-fold), bypasses the need for costimulation, and breaks tolerance against a model self-antigen in vivo. Our study opens the door to the application of synthetic, feedback-driven self-assembly platforms in immune modulation.