MicroRNA control of T cell development and function
- Steven Schaffert.
- Aug. 2013.
- Physical description
- online resource (xiv, 108 pages) : illustrations (some color)
- Schaffert, Steven.
- Chen, Chang-Zheng. thesis advisor (primary).
- Chien, Yueh-Hsiu. thesis advisor.
- Fathman, C. Garrison thesis advisor.
- Mellins, Elizabeth. thesis advisor.
- Stanford University. Program in Immunology.
- Stanford University. Committee on Graduate Studies. degree grantor.
- Includes bibliographical references (p. 103-108). 75 refs.
- 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.
- Publication date
- Submitted to the Program in Immunology and the Committee on Graduate Studies of Stanford University.
- Thesis (Ph.D.)--Stanford University, 2013.