Investigating mechanisms of bystander CD8 t cell mediated immunopathology
Active Project Grant Awarded Last action
- Award ID
- F30AI183705
- Recipient
-
Regents Of The University Of Minnesota UEI KABJZBBJ4B54
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $171,096
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 63% complete
- Place of performance
- Minnesota, USA
Award details come from USAspending.gov.
Description
- Abstract
- Defining mechanisms of CD8+ t cell immune dysfunction is critical to treating immune-mediated diseases. Bystander memory CD8+ t cells, in particular, are known to be protective to the host by supporting pathogen clearance and infection control early in an infection by producing and responding to pro-inflammatory cytokines and direct killing of infected cells. However, in some human disease contexts, dysregulation of bystander memory CD8+ t cells has led to immunopathology and poor disease outcomes. The factors that drive this phenomenon are unclear. We developed a mouse model to explore the pathological contexts and consequences of bystander memory CD8+ t cells. In our model, immunity to lymphocytic choriomeningitis virus (lcmv) leads to impaired control of an infection with the unrelated bacteria, listeria monocytogenes (LM). Our preliminary data indicate that mice carrying increased frequencies of lcmv-specific memory CD8+ t cells (P14 TCR transgenic cells) DIE following wild type (WT) LM. Additionally, our preliminary data suggest that exaggerated inflammation is not the cause of this pathology, as lcmv-immune mice did not have improved bacterial clearance compared to naïve controls and they had markedly elevated levels of serum IL- 10, an anti-inflammatory cytokine. We hypothesize that elevated IL-10 and lcmv-specific bystander memory CD8+ t cell sensitivity to IL-10 is central to dysregulated LM control in our model. Following this, abundant bystander memory CD8+ t cells cause fatal tissue damage by inappropriate cytolysis of uninfected cells, via innate-like mechanisms. I propose the following aims to test these hypotheses: aim 1 will identify the function of IL-10 during a bystander LM infection of lcmv-immune mice, by IL-10RA blockade and by ablating IL-10R on bystander memory CD8+ t cells. Aim 2 will determine the basis for bystander memory CD8+ t cell induced lethal immunopathology by modulating P14 TCR CD8+ t cells to ablate genes encoding key proteins involved in bystander immune responses. Together this proposal addresses an important knowledge GAP into mechanisms of immune dysfunction induced by bystander memory CD8+ t cells.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $0 | |
| Amendment | $564 | |
| Amendment | $564 | |
| Amendment | $42,492 | |
| Amendment | $0 | |
| Amendment | $42,492 | |
| Amendment | $0 | |
| Amendment | $42,492 | |
| Amendment | $42,492 | |
| Original award | $0 |
Quick answers
Who received award F30AI183705?
F30AI183705 was awarded to Regents Of The University Of Minnesota by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on May 29, 2025.
How much is award F30AI183705 worth?
$171,096 has been obligated on F30AI183705.
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