NIH/NIAID – Processing and Presentation of Non-Conventional MHC Ligands (R01, R21 Clinical Trial Not Allowed)

November 27, 2018 by School of Medicine Webmaster

The following description was taken from the R01 version of this FOA.

The purpose of this FOA is to stimulate research that will characterize antigen processing and presentation mechanisms used in the generation of novel peptidic and non-peptidic ligands presented by classical and non-classical MHC class I and class II molecules, and determine the contribution of these unique antigenic products to: protective immune responses to infectious pathogens; pathogen-associated immune pathogenesis; and/or in the induction/progression or prevention of immune-mediated diseases. These studies may facilitate the development of novel tools and reagents to advance design of immune-based therapeutics and vaccines.


The classic understanding of antigen processing and presentation begins with a protein fragment (peptide) associating with MHC molecules. Next, expression of the peptide-MHC complex at the cell surface allows for recognition by T cell receptors, which triggers T cell activation. The paths leading to peptide-MHC association differ for class I and class II MHC. MHC class I molecules present endogenous peptides derived from cytosolic processing of antigens or self-proteins. MHC class II molecules present peptides from exogenously derived proteins that are processed in phago-lysosomal compartments and trafficked to the cell surface. It has also been recognized that MHC class I molecules can access exogenous antigens and MHC class II molecules can access endogenous antigens and present peptides through a process called cross-presentation.

These long-accepted paradigms regarding antigen processing and presentation and T cell recognition are incomplete. Approximately 10% of antigenic peptides can be derived from unconventional sources including: alternative start codons; 3’ and 5’untranslated regions (UTRs); introns normally spliced during mRNA processing; exon splice variants; or covalent cross-linking of peptides to form hybrid peptide ligands. Additionally, the antigen components that trigger non-classical MHC I restricted CD8 T cells and unconventional or innate T cells, include lipids and small-molecule metabolites, but are not well characterized. This initiative will support research projects that seek to define novel antigen processing and presentation mechanisms used to generate these “non-classical and unconventional” T cell ligands and to understand the contribution of these novel antigen presentation products in protective immunity against infectious and immune-mediated diseases.

For this announcement, a ligand is the peptidic or non-peptidic antigenic determinant presented by MHC class I, MHC class II or non-classical MHC molecules that results in T cell activation.

Research Objectives and Scope

The objective of this research program is to promote the discovery of unique antigenic ligands (peptidic and non-peptidic) and understand the immune responses to these ligands. Characterization of the mechanisms used to generate such ligands and the T cell populations that recognize these products will facilitate a more comprehensive understanding of the mechanisms of T cell immunity, including generation and maintenance of T cell memory, in response to infectious or immune-mediated diseases. These studies also may facilitate the design and development of novel tools and reagents to advance immune-based therapeutics and vaccines.

Examples of research topics include, but are not limited to:

  • Studies of peptide ligands derived from translation initiated at codons other than the traditional methionine codon
  • Peptide ligands derived from non-contiguous sequences; hybrid peptides
  • Neoantigen ligands derived from post-translational modifications
  • Peptidic and non-peptidic ligands presented by non-classical MHC molecules (HLA-E, F, and G) and non-conventional molecules (e.g. CD1 family, MR1, TL)
  • Novel technologies to identify non-classical, non-conventional antigen presenting molecules and corresponding TCR usage

Research projects studying conventional antigen processing and presentation pathways are not appropriate for this PA and should utilize the Parent Funding Opportunity Announcement for NIH Research Project Grants or another suitable Funding Opportunity Announcement.

Note: This FOA uses the R01 grant mechanism, while the companion FOA, PA-19-066, uses the R21 mechanism. Applicants with preliminary data and/or planning longer-term studies may wish to apply using the R01 mechanism. High risk/high payoff projects that lack preliminary data or utilize existing data may be most appropriate for the R21 mechanism.



Filed Under: Funding Opportunities