# Influences of HLA Class I Polymorphisms on immune responses

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $561,310

## Abstract

Abstract
The major histocompatibility complex (MHC) class I gene locus in humans (human leukocyte antigens (HLA)
class I) is the most polymorphic of human genes. Individual variants have profound influences on disease
outcomes in infectious and inflammatory diseases and in cancer. HLA class I variants display distinct peptide
binding preferences which allows a diverse set of peptide antigens to be presented to T cell receptors (TCRs)
of CD8+ T cells. MHC class I molecules also play critical roles in the natural killer (NK) cell response via the
engagement of activating and inhibitory receptors of NK cells. In the textbook defined MHC class I assembly
pathway, peptides are derived from the cytosol of cells, transported into the endoplasmic reticulum (ER) via the
transporter associated with antigen presentation (TAP), and bound to MHC class I molecules in the ER in a
process edited by tapasin. This pathway is expected to culminate in the presentation of a stable repertoire of
high affinity peptide-MHC class I complexes on the cell surface. However, there is also a need to maintain
surveillance of endosomal compartments, as antigens derived from these compartments initiate CD8+ T cell
responses. Additionally, many HLA class I variants can assemble independently of components the classical
pathway. Some HLA class I allotypes are also found in complex with peptides that have broad predicted
affinity ranges, and present as imperfect and peptide-receptive forms in cells. There are fundamental
gaps in our knowledge about the non-canonical pathways that govern the formation of such molecules and
their functions in the immune response. It is our central hypothesis that a balance of canonical and non-
canonical HLA class assembly pathways is needed to enable both cytosolic and endosomal
surveillance, immunity in the face of pathogen evasion of the canonical pathway, and immunity under
conditions of inflammatory and nutritional stress. To address this hypothesis, the endosomal HLA class I
assembly pathway will be interrogated, to examine how specific factors affect the expression, localization,
and antigen presentation functions of different HLA class I allotypes. Additionally, assembly under tapasin
and TAP deficient conditions will also be examined, with a focus on their intersections with the
endolysosomal pathway, the resulting immunopeptidomes, and glycosylation changes to HLA class I
molecules. Together, these studies will unravel how HLA class I molecules maintain multicompartmental
immune surveillance and elucidate how the divergent assembly features of HLA class I allotypes ensure the
maintenance of immunity under pathogenic conditions. This knowledge will be important towards the
development of future immunotherapeutic strategies, by identifying features of HLA class I molecules that can
be exploited for enhanced immune protection.

## Key facts

- **NIH application ID:** 10977203
- **Project number:** 2R01AI044115-24A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** MALINI RAGHAVAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $561,310
- **Award type:** 2
- **Project period:** 1999-01-15 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10977203

## Citation

> US National Institutes of Health, RePORTER application 10977203, Influences of HLA Class I Polymorphisms on immune responses (2R01AI044115-24A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10977203. Licensed CC0.

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