Intestinal epithelial cell-T cell interactions governed by diet and changes in microbiota composition Open Access

Abstract

       The gut microbiota, a community of microbes that resides in the intestine, plays a key role in shaping host immune responses. Commensal-derived signals drive the differentiation of intestinal T cell populations that maintain intestinal homeostasis. Interactions between the microbiota and the immune system are bidirectional. While commensals help educate the immune system, the immune system in turn shapes microbiota composition. However, these interactions do not occur in isolation as they can be influenced by environmental factors such as the diet. Dietary fiber serves as a primary carbon source for commensal bacteria and is a key factor in controlling microbiota composition. Yet, how dietary fiber availability alters mucosal immune development through changes in the microbiota remains poorly understood.

The work in this dissertation defines mechanisms by which dietary fiber regulates small intestinal immune development through microbiota-dependent and epithelial cell-mediated pathways. Using dietary intervention approaches, this work demonstrated that a lack of dietary fiber consumption reshapes small intestinal microbiota composition, leading to the loss of Segmented Filamentous Bacteria (SFB) and as a result, impaired development of TCR⍺β⁺ CD8⍺β⁺, TCR⍺β⁺ CD8⍺⍺⁺ and TCR⍺β⁺ CD4⁺ CD8⍺⍺⁺ intraepithelial lymphocytes as well as lamina propria Th17 cells. This defect in T cell development persists over generations and cannot be restored by fiber supplementation alone, revealing that long-term low-dietary fiber consumption leads to the loss of key commensals and incomplete differentiation of the intestinal T cell landscape. Mechanistically, dietary fiber supports SFB-intestinal epithelial cell (IEC) interactions required to induce IFN𝛾 production by type 1 innate lymphoid cells (ILC1), which in turn induces MHC-II expression on IECs, required for the differentiation of CD4⁺ CD8⍺⍺⁺ intraepithelial lymphocytes (DP IELs). A low-fermentable fiber diet disrupts microbial balance by increasing Bifidobacterium pseudolongum abundance, which inhibits SFB colonization, disrupting this commensal-epithelium-immune cell crosstalk.

Overall, this dissertation establishes dietary fiber as a central regulator of the diet–microbiota–epithelial cell interactions that govern intestinal T cell development. These findings extend our knowledge of how nutritional and microbial cues integrate to sustain mucosal immune balance and provide a framework for future studies that aim to develop diet and microbiota based therapeutic strategies to restore immune homeostasis.

Table of Contents

Table of Contents

CHAPTER 1: INTRODUCTION ................................................................................................ 1

SECTION 1: MICROBIOTA ...................................................................................................... 2

SECTION 2: INTESTINAL INTRAEPITHELIAL LYMPHOCYTES .................................... 11

SECTION 3: INTESTINAL EPITHELIAL CELLS AND ANTIGEN PRESENTATION ....... 16

SECTION 4: SUMMARY ........................................................................................................ 20

SECTION 5: REFERENCES .................................................................................................... 21

CHAPTER 2: LOW DIETARY FIBER INTAKE IMPAIRS SMALL INTESTINAL TH17

AND INTRAEPITHELIAL T CELL DEVELOPMENT OVER GENERATIONS ............. 31

SECTION 1: ABSTRACT ........................................................................................................ 32

SECTION 2: INTRODUCTION ............................................................................................... 33

SECTION 3: RESULTS ............................................................................................................ 34

SECTION 4: DISCUSSION ..................................................................................................... 40

SECTION 5: MATERIALS AND METHODS ......................................................................... 43

SECTION 6: MAIN FIGURES ................................................................................................. 47

SECTION 7: SUPPLEMENTARY FIGURES .......................................................................... 58

SECTION 8: SUPPLEMENTARY TABLES ............................................................................ 60

SECTION 9: ACKNOWLEDGEMENTS AND AUTHOR CONTRIBUTIONS .................... 62

SECTION 10: REFERENCES .................................................................................................. 63

CHAPTER 3: DIETARY FIBER PROMOTES ANTIGEN PRESENTATION ON

INTESTINAL EPITHELIAL CELLS AND DEVELOPMENT OF SMALL INTESTINAL

CD4+ CD8⍺⍺+ INTRAEPITHELIAL T CELLS ...................................................................... 66

SECTION 1: ABSTRACT ........................................................................................................ 67

SECTION 2: INTRODUCTION ............................................................................................... 67

SECTION 3: RESULTS ............................................................................................................ 70

SECTION 4: DISCUSSION ..................................................................................................... 77

SECTION 5: MATERIALS AND METHODS ......................................................................... 83

SECTION 6: MAIN FIGURES ................................................................................................. 90

SECTION 7: SUPPLEMENTARY FIGURES ........................................................................ 103

SECTION 8: SUPPLEMENTARY TABLES .......................................................................... 113

SECTION 9: ACKNOWLEDGEMENTS AND AUTHOR CONTRIBUTIONS .................. 116

SECTION 10: REFERENCES ................................................................................................ 117

CHAPTER 4: DISCUSSION AND REMAINING QUESTIONS ........................................ 122

SECTION 1: CONCLUSIONS AND IMPLICATIONS ......................................................... 123

SECTION 2: REMAINING QUESTIONS ............................................................................. 125

SECTION 3: CONCLUDING REMARKS ............................................................................ 128

SECTION 4: REFERENCES .................................................................................................. 130

APPENDIX ................................................................................................................................ 131

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Microbiology & Molecular Genetics
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Cell Biology, Microbiology
Keyword	IELs Fiber Microbiota Immunology
Committee Chair / Thesis Advisor	Luisa Cervantes-Barragan, Emory University
Committee Members	Rheinallt Jones, Emory University Shonna McBride, Emory University Christopher LaRock, Emory University Joanna Goldberg, Emory University

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