[R21] Signal transduction mechanisms used by a group of uncharacterized ITAM- containing receptors in jawless vertebrates
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2028-06-30
Importo max: 233.444 EUR
Paese: US
Descrizione
PROJECT SUMMARY
Chimeric antigen receptors (CARs) are form of precision immunotherapy approved for the treatment of
hematologic malignancies. Nearly all CARs invariantly incorporate the same Immunoreceptor tyrosine-based
activation motifs (ITAMs) from human CD3 ZETA to stimulate the primary activation signal pathway in immune
cells (aka “Signal 1”). However, a one-size-fits-all approach likely does not trigger optimal Signal 1 activation
across different CAR applications/conditions. For example, excessive Signal 1 activation can result in toxicity by
“cytokine storm”, or CAR-T cell exhaustion. We propose that sequence-divergent ITAMs could activate cells with
varying kinetics or intensities, which would be beneficial for customizing CAR-based immunotherapy. In this
project, we investigate novel ITAMs sourced from the most distantly related species to humans that are thought
to utilize the ITAM mechanism in their immune systems: the Sea lamprey. Lampreys are jawless vertebrates that
feature an alternative form of adaptive immunity. In preliminary studies, we identified novel lamprey ITAMs, some
of which exhibit amino acid sequence differences that differ from the mammalian ITAM consensus sequence.
We hypothesize that these divergent ITAMs in CARs could activate cellular functions with varying strengths. The
significance of this unexplored field is that this work has the potential to reveal novel ITAMs that are beneficial
for immunotherapy and also to gain fundamental insights into the origins of adaptive immunity.
In Specific Aim 1, we will identify which of the previously uncharacterized ITAMs can activate a human
T cell. We will test this hypothesis with innovative “Mermaid” CARs, which consist of the extracellular and
transmembrane domains of human origin, fused to the cytoplasmic tails of lamprey ITAM-containing receptors.
We will analyze the capacity of these novel CARs to stimulate activating signals first in the Jurkat human T cell
line, then in primary human T cells. Preliminary studies indicate that this approach is feasible. The goal of
Specific Aim 2 is to identify the proteins that associate with ITAM containing receptors in primary lamprey
peripheral blood leukocytes. We will use the SH2 domains of SYK family kinases to pull-down lamprey ITAM
containing receptors and identify these proteins by mass spectrometry. This work will confirm the binding
specificity of these divergent ITAM domains.
Impact: At the conclusion of these studies, we will know which of the novel lamprey ITAMs can function
in a human T cell system. The knowledge gained from this work will expand the “toolbox” of potential ITAMs that
can be used to modulate the intensity or kinetics of CAR signaling. This work will also open a new area of immune
receptor biology by identifying the receptors that utilize ITAMs in the jawless vertebrate adaptive immune system.
This work will provide new insights into how the mechanisms used by our immune receptors may have originate
Istituzione: EMORY UNIVERSITY
PI: Byron Benton Au-Yeung
Progetto: 1R21AI196701-01A1
Settori: National Institute of Allergy and Infectious Diseases
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