Developmental acquisition of memory-phenotype CD8+ t cell function in infection and cancer
Active Project Grant Awarded Last action
- Award ID
- F30AI183709
- Recipient
-
The University Of Chicago UEI ZUE9HKT2CLC9
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $218,164
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 33% complete
- Place of performance
- Chicago, IL 60637, USA
Award details come from USAspending.gov.
Description
- Abstract
- In unprimed specific pathogen free and germ-free mice, there exists a population of ΑΒ CD8+ t-cells that exhibit hallmarks of agonist ligand encounter, termed CD8 memory phenotype (CD8-MP) cells. These cells account for ~10% of the CD8+ t cell repertoire in adult mice, have a CD44HICD122+ phenotype, display other memory markers shared by 'true memory' CD8+ t cells (CD8-TM) generated in response to pathogen challenge, and have incompletely defined functions. Previously, CD8-MP cells were thought to develop in the periphery due to subthreshold t-cell receptor (TCR) signaling to non-cognate self-antigen and in response to cytokine signaling. However, recent work from our lab demonstrated that CD8-MP differentiation is a robust and conserved TCR- instructed process driven by the recognition of agonist self-ligands in the thymus and consolidated in the periphery. Importantly, we also demonstrated that select CD8-MP-biased clones are recurrently enriched in oncogene-driven prostate tumors and express high densities of PD-1, suggesting a previously unappreciated role for CD8-MP cells in the immune response to cancer. The objective of this proposal is to define the immunological mechanisms driving the differentiation of CD8-MP cells and the functional potential imparted by this process by analyzing CD8-MP functional activity in settings of infection and cancer. We will test the hypothesis that the differentiation of CD8-MP cells is a two-step process, triggered by the recognition of self- pmhc-i antigen displayed by medullary thymic epithelial cells (mtecs), followed by sensing of MHC-i and IL- 15 in the periphery, which confer CD8-MP cells with a unique "non-cytolytic" functional profile. In aim 1, we will define the antigen presenting cells and accessory signals directing the differentiation of CD8-MP cells at both a polyclonal and monoclonal level, utilizing our TCR "retrogenic" mouse pipeline and our previously identified naturally occurring CD8-MP biased clones. In aim 2, we will identify CD8-naïve and CD8-MP-biased clones reactive to the same model antigen and utilize our tcrrg pipeline to interrogate the function of these cells following agonist ligand encounter in a tumor model and in other inflammatory contexts. Elucidating these mechanisms will provide needed insight into the biology of this prevalent t cell subset and will have key implications for our understanding of self-tolerance and cancer.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $55,114 | |
| Amendment | $564 | |
| Amendment | $564 | |
| Amendment | $53,974 | |
| Amendment | $53,974 | |
| Original award | $53,974 |
Quick answers
Who received award F30AI183709?
F30AI183709 was awarded to The University Of Chicago by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on August 25, 2025.
How much is award F30AI183709 worth?
$218,164 has been obligated on F30AI183709.
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