The Role of the Glucocorticoid Receptor in CD8+ T cells Open Access

Giarracco, Emma (Spring 2022)

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Exogenous glucocorticoid (corticosterone) administration is a common therapeutic in cancer patients due to its ability to reduce inflammation and manage pain. Commonly dexamethasone—which reduces overall inflammation by lowering the activity of the immune system and slowing the body’s response to disease or injury— is used in combination with a wide variety of cancer treatments to help mitigate the side effects of cancer or its treatment. Immunology-based cancer treatments rely on immune activation and re-functionalization to respond to cancer and other chronic infections. It is predicted that steroid administration has a negative impact on the efficacy of immunology-based cancer treatments. Glucocorticoids can be examined using the murine lymphocytic choriomeningitis virus (LCMV) model. Previous studies (Acharya et al., 2020) indicate that glucocorticoids —when acting through the glucocorticoid receptor (GR) —modulate immune function and the immune response. Their effect ranges from cytokine suppression, and alteration of thymocyte development, to immunosuppression. GR causes transcriptional changes via direct DNA binding, and in turn, controls otherwise lethal immune activation. In this research the role of GR in immune activation is studied through the generation of GR T cell knockout (KO) mice, allowing us to study the role of GR in only activated CD8+ T cells. We find that the Cluster of Differentiation 8 (CD8+) T cell glucocorticoid receptor (GR) is required for survival of the chronic (clone 13) LCMV infection. These data also show increased interferon-γ (IFN-γ) levels in P14 KO mice after chronic viral infection in the clone 13 strain of LCMV. Through P14 LCMV T Cell Receptor (TCR) transgenic mice and congenic markers, we can characterize the GR signaling pathway in CD8+ T cells throughout the course of chronic infection, giving better insight into the interaction between GR and immunotherapy and improving the efficacy of future treatments dependent on immune activation.

Table of Contents

Table of Contents

Introduction 1

Figure 1: HPA axis 2

Figure 2: Differentiation pathway of CD8+ T cells with Tim3 and CX3CR1 markers 5

Methods 8

Results 13

Figure 3: Glucocorticoids are elevated after chronic infection with LCMV clone 13 14

Figure 4: The CD8+ T cell glucocorticoid receptor (GR) is required for survival of LCMV 15

Figure 5: GRfl/fl gzmb cre+ mice have elevated levels of IFN-γ at day 7 17

Figure 6: Adoptive transfer experiment using CD45 transgenic markers in P14 mice 18

Figure 7: P14 KO CD8+ T cells expand preferentially over WT 19

Figure 8: Differentiation pathway in CD8+ T cell exhaustion with intracellular Tcf-1 and extracellular Klrg1 marker 21

Figure 9: Examples of Tcf-1 vs Klrg1 staining 22

Figure 10: No significant difference in Tcf-1 expression between P14 KO and WT cells 23

Figure 11: Expression of CD8+ T cell functional markers Ki-67, Gzmb, and Tox on P14 KO and WT cells 24

Figure 12: TIGIT is expressed preferentially in P14 WT cells 26

Figure 13: CD226 is expressed preferentially in P14 KO cells 27

Figure 14: RNA sequencing on P14 KO and WT cells 28

Figure 15: Example RNA sequencing data for three selected genes 29

Conclusion 30

Discussion and Future Direction 31

References 34

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