Landy, Emily
(2023)
Cytokines and cytotoxicity: Dissecting susceptibility to lethal hyperinflammation.
Doctoral Dissertation, University of Pittsburgh.
Abstract
Hemophagocytic Lymphohistiocytosis (HLH) and Macrophage Activation Syndrome (MAS) are life-threatening hyperinflammatory syndromes. Familial HLH is caused by genetic impairment of granule-mediated cytotoxicity (e.g., perforin-deficiency). MAS is linked to excess activity of the inflammasome-activated and pro-inflammatory cytokine Interleukin 18 (IL-18). Both diseases share a similar set of clinical phenotypes such as hepatosplenomegaly, anemia, hemophagocytosis, and recurrent fevers. Patient samples from multiple organs show enhanced numbers of activated CD8 T cells. Together this suggests that these hyperinflammatory diseases (and maybe others) share a common pathogenic pathway. Additionally, burgeoning evidence suggests that heterozygous defects in cytotoxicity can predispose patients with other rheumatic diseases to a hyperinflammatory status. Understanding the underlying mechanisms of hyperinflammation is necessary for quality patient treatment to these deadly diseases. To study these mechanisms, we employ mouse models of hyperinflammation, in mice with either perforin deficiency (Prf1-/-) or excess IL-18 (Il18tg) have little to no clinical features on their own/without provocation. However, when infected with LCMV these mice exhibit hyperinflammation nearly identical to that of HLH and MAS patients. Additionally, mice with dual susceptibility (Prf1-/-Il18tg; DS) succumb to spontaneous, lethal hyperinflammation. We hypothesized that these factors converged on pathogenic hyperactivated CD8 T cells with a decreased activation threshold, amplified cytokine response, and extended lifespan.
In Il18tg mice, IL-18 effects on CD8 T cells drove MAS following a viral (LCMV), but not innate (TLR9), trigger. In vitro, CD8 T cells required TCR stimulation to fully respond to IL-18, and Prf1-/- cells were resistant to restimulation-induced cell death (RICD). Concomitant with hyperinflammation, dual susceptibility mice developed massive post-thymic oligoclonal CD8 T cell expansion in their spleens, livers, and bone marrow detectable even in Prf1+/-Il18tg mice. These cells proliferated, produced excessive IFNγ, but also expressed receptors and transcription factors associated with exhaustion. In addition, DS mice with a restricted TCR repertoire still developed spontaneous HLH and were strongly enriched for T cells not expressing the transgenic TCR.
Together, these data suggest that hyperinflammation is a result of a unique, unrelenting, and targetable state of CD8 T cell hyperactivation that is terminal, pathogenic, and has an activation state combining features of exhaustion and effector function.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Published |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
22 September 2023 |
| Date Type: |
Publication |
| Defense Date: |
3 November 2023 |
| Approval Date: |
22 March 2024 |
| Submission Date: |
7 November 2023 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
171 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Microbiology and Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Hyperinflammation, IL-18, CD8 T cell, Perforin |
| Type of Data: |
Other |
| Date Deposited: |
22 Mar 2024 20:23 |
| Last Modified: |
22 Mar 2024 20:23 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/45415 |
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