# Delineating the non-conventional MHC class I and class II peptidome of influenza

> **NIH NIH R21** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $209,990

## Abstract

PROJECT SUMMARY
A cornerstone of adaptive immune responses to infectious agents, cancers and self-tissues is the activation of
CD4+ and CD8+ T cells by antigen-derived peptides (epitopes) complexed with Major Histocompatibility Complex
class II and class I molecules (MHC-II and -I), respectively. Accordingly, identification of T cell-activating peptides
is frequently a critical step in the development of rational prophylactic and therapeutic strategies. Most methods
for identification are guided by the prevailing view that peptides are excerpted from the products of conventional
transcription, RNA processing and translation. However, we and other labs have demonstrated that MHC-I- and
-II-bound peptides can be derived from a wide array of non-canonical mechanisms, including initiation of
translation in an alternative reading frame, initiation at a non-AUG codon, co-translational frameshifting, and
proteasome-mediated post-translational peptide splicing. Currently, non-conventional epitopes are of peripheral
interest, perhaps because many fundamental questions concerning their significance remain unanswered. We
do not understand: 1) the fraction of all presented peptides that are non-conventional, 2) whether all the
mechanisms underlying non-canonical peptide production have been described, 3) the relative frequencies with
which different mechanisms produce non-conventional epitopes, 4) the extent to which non-conventional
epitopes drive T cell responses to infectious agents, cancers and self-antigens, and, 5) the prevalence of MHC-
II-presented non-canonical peptides, most examples thus far being MHC-I-restricted. With respect to question
4, a recent publication and our preliminary data indicate that non-canonical peptides can drive strong,
immunodominant T cell responses. With respect to question 5, the Eisenlohr lab has developed a model of MHC-
II-restricted peptide production that is far more complex than generally envisioned. Thus, many of the
mechanisms that produce MHC-I-restricted non-conventional epitopes should apply to MHC-II. Through a highly
complementary collaboration between the Eisenlohr and Ternette labs, via cutting-edge mass spectrometry,
well-developed immune recognition assays, and an array of methods to identify mechanisms underlying non-
conventional epitope expression, we will test the hypothesis that both MHC-I and MHC-II non-canonical epitopes,
produced by a variety of mechanisms, drive a substantial portion of the TCD8+ and TCD4+ responses to influenza.
In addition to potentially uncovering new fundamental cell biology, outcomes could substantially alter the view of
host defenses against a high priority infectious disease, pointing to new prophylactic and therapeutic strategies.
In addition, we envision the work launching several lines of future investigation, including: 1) assessing the
protective capacities of non-conventional epitope-specific T cells, 2) elucidating the antigen processing
machinery that produces non-...

## Key facts

- **NIH application ID:** 10171775
- **Project number:** 5R21AI153978-02
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Laurence Crane Eisenlohr
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $209,990
- **Award type:** 5
- **Project period:** 2020-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10171775

## Citation

> US National Institutes of Health, RePORTER application 10171775, Delineating the non-conventional MHC class I and class II peptidome of influenza (5R21AI153978-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10171775. Licensed CC0.

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