[R01] Decoding the specificity of human T cell allorecognition
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2031-07-31
Importo max: 856.216 EUR
Paese: US
Descrizione
SUMMARY Direct CD8+ T cell recognition of allo-HLA plays a major role in acute cellular rejection (ACR) of
transplanted tissues. However, much is unknown about the T cells responsible for direct ACR. For decades,
alloreactive T cells have been viewed as generally nonspecific, responding either to a plethora of allopeptides in
the context of allo-HLA, or unique determinants on allo-HLA independent of peptide. Recent data though has
suggested that many, if not most, alloreactive T cells are allospecific, responding to individual peptide/HLA
complexes. Despite these advances, and despite their critical role in transplant rejection, systematic
studies of intragraft T cells, their specificities, and their fundamental biology are lacking. We now have
an unprecedented opportunity to study the T cells driving direct ACR. Our initial work using scRNA sequencing
on biopsies and urine from 10 patients undergoing kidney transplant rejection found a surprisingly limited
number (~20/patient) of clonally expanded CD8+ T cells (CD8EXP) with unique CDR3 α/β sequences.
Remarkably, some of these CD8EXP persist for months in rejecting allografts, despite histologically successful
anti-rejection therapy. In some cases, these “rogue” cells can re-expand and contribute to additional rejection
episodes. However, the specificities, transcriptomic programs, functionality, and environmental niches that favor
persistence of these and other CD8EXP remain unclear. We are now poised to make substantial
breakthroughs in these critical areas. Supported by a wealth of exciting preliminary data demonstrating both
rigor and feasibility, the goals of this project are to capitalize on our discoveries to advance our understanding of
the specificity and biology of CD8+ T cells driving ACR. In our 1st Aim, we will determine the specificities of
intragraft CD8EXP from several patients undergoing kidney allograft rejection, allowing us to decode the
underpinnings of allospecificity, including its structural and biochemical features, the contributions of TCR affinity
and specificity to persistence of CD8EXP cells, and the potential for shared or immunodominant targets in patients
with the same HLA mis-matches. In preliminary data for Aim 1, in what we believe is a first for the field, using
yeast display coupled with state-of-the-art structural informatics, we identified a bona fide allopeptide that
evokes a prominent response from one of these allospecific TCRs. In our 2nd Aim, we will define the spatially
resolved environments and cell-cell communications that define the gene expression and functional states of
persisting, intragraft, allospecific CD8EXP cells. Overall, we will greatly expand our knowledge of the T cells driving
ACR. We will identify the ligands of T cells driving rejection, assess the potential for immunodominance, and
deconstruct the biochemistry of TCR allospecificity. We will dissect the phenotypes and genetic programming of
the allospecific T cells that are retained
Istituzione: UNIVERSITY OF NOTRE DAME
PI: Brian M Baker, David A Hildeman
Progetto: 1R01AI201785-01
Settori: National Institute of Allergy and Infectious Diseases
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