MicroRNA control of T cell development and function
- Much has been learned about the molecular and cellular components critical for the control of immune responses and tolerance. It remains a challenge, however, to control the immune response and tolerance at the system level without causing significant toxicity to normal tissues. Recent studies suggest that microRNAs (miRNAs), an abundant class of ~22 nucleotides regulatory RNAs, play important roles in immune cells. In this thesis, I examined the function of miR-181 genes in regulating T cell selection, development, and immune tolerance. We show that genetic ablation of mir-181a-1/b-1 ---- a T cell sensitivity tuner ---- in double-positive (DP) thymocytes dampens TCR and Erk signaling and affects positive selection. Moreover, dampening TCR signaling as the result of mir-181a-1/b-1 deletion potentiates the reactivity of self-specific T cells without significantly affecting the pool sizes of naive T cells recognizing specific self-antigens. Finally, loss of mir-181a-1/b-1 in peripheral T cells reduces their basal TCR signaling and their ability to migrate from lymph nodes to the pathogenic sites during autoimmune perturbations. Interestingly, loss of mir-181a-1/b-1 results in quantitative defects in various T and B lymphocyte populations, but does not cause major structural damage to the immune system or spontaneous autoimmunity. Our findings illustrate that mir-181a-1/b-1 controls tolerance through opposing activities in selection and peripheral T cell function. Thus, despite the subtle effects of miRNAs on gene expression, miRNAs have the potential to influence the outcomes of normal and pathogenic immune responses by controlling the quantitative and dynamic aspects of immune responses.
|Type of resource
|electronic; electronic resource; remote
|1 online resource.
|Stanford University, Program in Immunology.
|Fathman, C. Garrison
|Fathman, C. Garrison
|Statement of responsibility
|Submitted to the Program in Immunology.
|Thesis (Ph.D.)--Stanford University, 2013.
- © 2013 by Steven Anthony Schaffert
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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