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The Role of Dendritic Cells in the Generation of CD8+ T Cell Responses During Cryptosporidium Infection Breanne E Haskins
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Haskins, Breanne E., author.
- Language:
- English
- Subjects (All):
- Immunology.
- Microbiology.
- Cellular biology.
- Parasitology.
- 0982.
- 0410.
- 0379.
- 0718.
- Local Subjects:
- Immunology.
- Microbiology.
- Cellular biology.
- Parasitology.
- 0982.
- 0410.
- 0379.
- 0718.
- Physical Description:
- 1 electronic resource (146 pages)
- Contained In:
- Dissertations Abstracts International 86-07B
- Place of Publication:
- Ann Arbor : ProQuest Dissertations and Theses, 2024
- Language Note:
- English
- Summary:
- Cryptosporidium is an intracellular intestinal parasite that causes debilitating diarrheal disease in individuals with primary and acquired defects in T cell function. However, because of a paucity of tools to study parasite-specific responses it has been a challenge to understand how this infection generates T cell responses and how they mediate parasite control. In Chapter 2, Cryptosporidium was engineered to express a parasite effector protein (MEDLE-2) that contains the MHC-I restricted SIINFEKL epitope which is recognized by TCR transgenic OT-I CD8+ T cells. These modified parasites induced expansion of endogenous SIINFEKL-specific and OT-I CD8+ T cells that were a source of IFN-γ that could restrict growth of Cryptosporidium. This T cell response was dependent on the translocation of MEDLE-2 into the host cell and similar results were observed with the secreted parasite effector ROP1. Although infection and these translocated effector proteins are restricted to intestinal epithelial cells (IEC), type I dendritic cells (cDC1) were required to generate CD8+ T cell responses to these model antigens. In numerous experimental settings, the ability of the cDC1 subset of dendritic cells (DCs) to present antigen, provide a platform for CD4+ T cell help canonically mediated by CD40L, and produce the cytokine IL-12 are associated with the activation and maintenance of CD8+ T cells. The studies in Chapter 3 revealed that CCR7 was required for DC migration from infected gut to the mesenteric lymph nodes and the ability of cDC1s to express MHC-I was critical for priming of OT-I cells. These early events were dependent on CD40/CD40L signaling but independent of the ability of cDC1 to produce IL-12p40 or CD4+ T cells. Thus, only a subset of canonical functions of cDC1 are required to generate CD8+ T cell responses to Cryptosporidium. Additionally, while the loss of MHC-I expression on enterocytes did not alter OT-I priming, it was required in the intestine for optimal parasite control. Together, these data sets highlight Cryptosporidium effectors as potential targets of the immune system and suggest a model in which CD8+ T cells require sequential MHC-I signals provided by cDC1 and IEC to provide protection against Cryptosporidium
- Notes:
- Source: Dissertations Abstracts International, Volume: 86-07, Section: B.
- Advisors: Hunter, Christopher A. Committee members: Eisenlohr, Laurence; Henrickson, Sarah E.; Abt, Michael C.
- Ph.D. University of Pennsylvania 2024
- Local Notes:
- School code: 0175
- ISBN:
- 9798302185211
- Access Restriction:
- Restricted for use by site license
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