University of Notre Dame

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Understanding Peptide-Specific Recognition between Immune Receptors and Peptide-Major Histocompatibility Complexes

posted on 2024-03-25, 01:56 authored by Jiaqi Ma

The immune system plays a key role in defending the host against a variety of pathogenic infections from the outside world. As an important pathway in the immune system, antigen presentation process facilitated by major histocompatibility complex (MHC) proteins aids in both the innate and adaptive immunity of vertebrates. In the adaptive immunity, MHC proteins present different peptide antigens degraded from intracellular proteins onto the cell surface for T cell immune surveillance. And because of its vital importance in representing the internal environment in the form of the peptide-MHC (pMHC) complexes, an adequate level of MHC expression on the cell surface is one indicator of a healthy cell and protect the cell from being lysed by natural killer (NK) cells in the innate immunity. Due to the variety of its jobs, the pMHC complex can be recognized by different immune receptors through different patterns.

In general, functional T cells recognize the pMHC complex, binding on “top” of the peptide fragment as well as the peptide binding groove of the MHC molecule via its T cell receptor (TCR). Each TCR possesses specificity for a limited repertoire of pMHCs and thus senses differences in presented peptides. In terms of NK cells, however, NK receptors focus mainly on the MHC molecules and pay little to no attention to the presented peptides. The NK receptor Ly49C, for example, recognizes pMHCs underneath the floor of peptide binding groove and does not make direct contacts to peptides that are presented. In spite of this, the Ly49C receptor can still sensing pMHCs with different peptides and exhibits a degree of peptide specificity.

In this dissertation, I seek to understand the mechanisms of the peptide specificity shown by different immune receptors using structural and biophysical methods. For the Ly49C receptor, I found that the peptide sensitivity of Ly49C is due to dynamic allostery of pMHC molecules influenced by different bound peptides. For TCRs, I examined the immunogenicity of a neoantigen derived from the PIK3CA oncogene and showed that its distinction comes from not only the higher stability compared to its wild-type counterpart, but also its ability to undergo conformational transitions and present a distinct surface that is recognizable to TCRs. Overall, my findings greatly expand our understanding of specificity in immune recognition.


Date Modified


Defense Date


CIP Code

  • 26.0202

Research Director(s)

Brian M. Baker

Committee Members

Holly Goodson Sharon Stack


  • Doctor of Philosophy

Degree Level

  • Doctoral Dissertation

Alternate Identifier


OCLC Number


Program Name

  • Chemistry and Biochemistry

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