The thymus produces an abundance of MHC restricted, self-tolerant CD4 helper and CD8 cytolytic T cells to participate in adaptive immune responses. Such ?conventional T cells? develop in response to low-affinity TCR interactions with MHC molecules that display a diversity of self-peptides in the cortical region of the thymus. In contrast, high affinity interactions result in clonal deletion, but can also support the survival and differentiation of mature regulatory effectors in some contexts. These effectors include foxP3+ natural regulatory T cells (Treg), intraepithelial lymphocytes (IEL), and CD1d restricted natural killer T cells (NKT). This proposal will explore the role of high-affinity TCR signaling in clonal deletion and NKT effector differentiation. In the previous period we developed a novel approach to capturing T cell clones that are normally destined for deletion. Here we apply this approach to study the repertoire, reactivity, and structure of clones deleted at the early (DP) stage versus those deleted at the late (SP) stage. Specifically we hypothesize that early deleted clones have a distinct interaction with MHC that is less dependent on peptide, whereas late deleted clones have classic peptide-MHC reactivity. Experiments are proposed that will characterize the distinct autoimmune pathologies created by the escape of early versus late deleted clones. Lipid-specific natural killer T cells (NKT) are derived from thymic progenitors that survive strong signaling in the thymus and develop into 3 major effector subsets that produce distinct cytokines, as we showed in the previous period. One of these subsets (NKT2) produces IL-4 in the steady state and this influences multiple aspects of immune cell development to promote type II immune responses. Our research will identify key molecules controlling the differentiation of NKT cells; further characterize the effects of NKT2 produced IL-4 on lymphoid, myeloid, and stromal cells; and define how NKT cells traffic to unique tissue environments to impact immune responses.

Public Health Relevance

This proposal seeks to understand how TCR signaling during T lymphocyte development instructs various nave and effector lineages. Strong signaling can cause clonal elimination of dangerous T cells or survival and effector differentiation of regulatory cells. Understanding the nature of each is important basic knowledge and could inform about the pathogenesis of different types of autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI039560-22
Application #
9393955
Study Section
Special Emphasis Panel (NSS)
Program Officer
Prabhudas, Mercy R
Project Start
2016-12-01
Project End
2021-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
22
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pathology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Breed, Elise R; Lee, S Thera; Hogquist, Kristin A (2017) Directing T cell fate: How thymic antigen presenting cells coordinate thymocyte selection. Semin Cell Dev Biol :
Ruscher, Roland; Kummer, Rebecca L; Lee, You Jeong et al. (2017) CD8?? intraepithelial lymphocytes arise from two main thymic precursors. Nat Immunol 18:771-779
Lee, You Jeong; Starrett, Gabriel J; Lee, Seungeun Thera et al. (2016) Lineage-Specific Effector Signatures of Invariant NKT Cells Are Shared amongst ?? T, Innate Lymphoid, and Th Cells. J Immunol 197:1460-70
Hogquist, Kristin A; Xing, Yan; Hsu, Fan-Chi et al. (2015) T Cell Adolescence: Maturation Events Beyond Positive Selection. J Immunol 195:1351-7
Fulton, Ross B; Hamilton, Sara E; Xing, Yan et al. (2015) The TCR's sensitivity to self peptide-MHC dictates the ability of naive CD8(+) T cells to respond to foreign antigens. Nat Immunol 16:107-17
Lee, You Jeong; Wang, Haiguang; Starrett, Gabriel J et al. (2015) Tissue-Specific Distribution of iNKT Cells Impacts Their Cytokine Response. Immunity 43:566-78
Lee, June-Yong; Skon, Cara N; Lee, You Jeong et al. (2015) The transcription factor KLF2 restrains CD4? T follicular helper cell differentiation. Immunity 42:252-264
Sawicka, Maria; Stritesky, Gretta L; Reynolds, Joseph et al. (2014) From pre-DP, post-DP, SP4, and SP8 Thymocyte Cell Counts to a Dynamical Model of Cortical and Medullary Selection. Front Immunol 5:19
Klein, Ludger; Kyewski, Bruno; Allen, Paul M et al. (2014) Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see). Nat Rev Immunol 14:377-91
Holzapfel, Keli L; Tyznik, Aaron J; Kronenberg, Mitchell et al. (2014) Antigen-dependent versus -independent activation of invariant NKT cells during infection. J Immunol 192:5490-8

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