# Signaling via MHC: engineering immune cells with new capabilities

> **NIH NIH DP2** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $1,383,783

## Abstract

ABSTRACT
T cells constitute an essential arm of the adaptive immune system, protecting against pathogens and tumors,
while tolerating self-tissues. Dysregulation of T cell responses can lead to infectious diseases, cancers, or
autoimmune disorders. The key to the effectiveness of T cells is their exquisite antigenic specificity, which can
be harnessed to combat diseases. T cells use their surface T cell receptor (TCR) to recognize peptide epitopes
on Major Histocompatibility Complex (MHC) molecules (pMHC). While signaling through the TCR and its
consequences have been studied extensively, pMHC is conventionally seen as merely a ‘flag’ on target cells for
recognition by T cells. MHC molecules do not have canonical intracellular signaling domains, and therefore do
not elicit any function into the cells presenting them, making TCR-pMHC interaction a ‘one-way street’ in terms
of functional response. This presents a unique engineering opportunity: can TCR-pMHC interactions become
‘two-way streets’? Here, we hypothesize that if pMHC complexes are augmented with signaling domains, they
can elicit signaling cascades, leading to expression of response genes that will cause cell-intrinsic functional
changes, ultimately leading to cell-extrinsic functional changes. To that end, we will use the engineering platform
developed by my group: Signaling and Antigen-presenting Bifunctional Receptors (SABRs). SABRs consist of
extracellular full-length MHC complexes with genetically (and hence covalently) linked epitopes, fused with
intracellular signaling domains. SABRs can present epitopes to T cells and elicit intracellular signaling upon
successful recognition, thereby converting TCR-pMHC interactions into ‘two-way streets. In this proposal, we
aim to wield SABRs to impart novel functional capabilities to immune and non-immune cells, thereby opening a
new frontier of immune engineering and synthetic immunology. We will first lay out a framework for developing
SABRs as a cellular engineering platform to empower combinatorial engineering of immune and non-immune
cells to achieve desired immune outcome. We will describe three immune applications of SABRs: 1) engineering
of cytotoxic CD8+ T cells or Natural Killer (NK) cells to eliminate autoreactive CD4+ T cells, 2) engineering
professional Antigen-Presenting Cells (APCs) to modulate self-reactive or anti-tumor CD8+ T cell responses, 3)
engineering CD8+ T cells to sense endogenous immunity to specific antigens and induce a secondary function,
leading to a ‘read-and-react’ molecular circuit. These studies will create cellular therapeutic modalities, immune
monitoring and perturbation tools, experimental model systems and uncover new immune phenomena. These
studies will have profound implications on study and treatment of a wide range of diseases – autoimmune
disorders, infectious diseases, cancers, and organ transplantations.
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## Key facts

- **NIH application ID:** 10472922
- **Project number:** 1DP2AI176138-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Alok Joglekar
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,383,783
- **Award type:** 1
- **Project period:** 2022-09-07 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10472922

## Citation

> US National Institutes of Health, RePORTER application 10472922, Signaling via MHC: engineering immune cells with new capabilities (1DP2AI176138-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10472922. Licensed CC0.

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