The role of selenoproteins and CCR10 in immune cell homeostasis
Open Access
- Author:
- Lyu, Pingyun Yun
- Graduate Program:
- Pathobiology
- Degree:
- Master of Science
- Document Type:
- Master Thesis
- Date of Defense:
- July 07, 2020
- Committee Members:
- Girish Soorappa Kirimanjeswara, Thesis Advisor/Co-Advisor
Joyce Jose, Committee Member
Anthony Paul Schmitt, Committee Member
K. Sandeep Prabhu, Committee Member
Anthony Paul Schmitt, Program Head/Chair - Keywords:
- Selenium
Selenoproteins
B cells
Obesity
IFN
CCR10
ITIM
SHP-1
T cells
Macrophage
Skin
Trspfl/flCD19cre/wt
Trspfl/flLysMcre/wt
CCR10-/- - Abstract:
- Selenium (Se) is an essential trace element that functions by being incorporated into selenocysteine—a necessary amino acid for the synthesis of selenoproteins. Selenoproteins are involved in a variety of biological processes, including antioxidant response, redox homeostasis, thyroid hormone metabolism, and protein folding. My work in Dr. Girish Kirimanjeswara’s laboratory has primarily focused on understanding the role of Se in immune cells, as well as exploring the functional implications of immune cell specific selenoproteins in obesity and viral infection. Previous studies have shown that one of the hallmarks of obesity is systemic or local inflammation in the gut and adipose tissues. Obesity-induced inflammation is detrimental and results in insulin resistance. This is reported to be caused, at least partially, by the functional and phenotypic changes of B cells. However, the cellular mechanisms governing the changes of B cells in obese conditions remain unclear. A previous study has shown that diet-induced obesity impairs the numbers of splenic B cells by inducing oxidative stress, which coincides with the reduction of selenoproteins in these cells. These observations lead to the hypothesis in Chapter 2 that selenoproteins play a protective role against obesity by regulating B cell function and homeostasis. Consistent with this hypothesis, we observed a significant increase in body weight gain in mice on high fat diet that had B cell-specific selenoproteins knockout (TrspB mice) as compared to wild-type (WT) littermates. The increase of body weight in TrspB mice was in accordance with several functional and phenotypical changes in B cells. First, the deficiency of selenoproteins in a B cell-specific manner, altered the percentage of gastrointestinal IgA producing cells, and this subsequently resulted in abnormal fecal IgA production. In addition to fecal IgA, we also observed a drastic reduction of secreted IgM in TrspB mice. Furthermore, a shift of immune cell homeostasis has been identified in TrspB mice in different segments of the intestine. Collectively, the data from Chapter 2 suggest that B cell-specific selenoproteins prevent obesity by maintaining B cell functions and homeostasis. In Chapter 3, we investigated the role of Se in regulating the host immune response against viral infections. Here we show that Se supplementation enhanced the expression of type I and type III interferons (IFNs) in bone marrow-derived macrophages (BMDMs) in response to Poly(I:C) stimulation. Furthermore, IFNs were more robustly induced by Poly(I:C) in BMDMs from WT mice compared to BMDMs from macrophage-specific selenoproteins knockout mice (TrspM). The supplementation of sodium selenite into BMDM cultures of TrspM cells failed to rescue the impaired IFNs expression. Taken together, these observations highlight the antiviral function of Se. Mechanistically, selenoproteins expressed by macrophages are required for the induction of type I and type III IFNs in response to viral infection. My work in Dr. Na Xiong’s laboratory shown in Chapter 4 focuses on the molecular mechanisms by which CCR10 regulates the homeostatic establishment of skin T cells. Previous studies showed that CCR10-knockout (CCR10-/-) mice displayed disrupted skin T cell homeostasis. Here we used a murine stem cell virus (MSCV)-based retroviral expression system to overexpress wild-type CCR10 in CCR10-/- T cells. Compared to the empty viral vector, CCR10-/- T cells transduced with the CCR10 overexpression vector increased the specific migration of T cells in vitro in response to its skin-specific ligand CCL27. When transferred into T cell-deficient Rag1-/- mice, T cells transduced with wild-type CCR10 restored the homeostatic establishment in the skin with higher Treg/Teff ratio. Next, we identified a putative immunoreceptor tyrosine-based inhibition motif (ITIM) within CCR10 which is required for maintaining the homeostasis of regulatory and effector T cells in the skin by activating Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1). Mutation of ITIM in CCR10 impaired the activation of SHP-1, blocked the in vitro migration of T cells, and impaired the establishment of the skin T cell repertoire. These data provide new insight into the function of CCR10 in regulating skin T cell homeostasis.