Unlike alpha/beta T cells, gamma/delta T cells preferentially reside in epithelial tissues covering the external and internal surface of a body, where they function in the first line of defense, such as regulation of inflammation, tumor surveillance and tissue repairing. Using transgenic and knockout mouse models as experimental approaches, we will try to uncover molecular mechanisms underlying development and specific tissue distribution of gamma/delta T cells in the skin. Nearly all skin gamma/delta T cells express identical Vgamma3/Vdelta1 T cell receptors and originate from the fetal thymus. Positive selection of gamma/delta T cells in the fetal thymus is associated with a coordinate switch in expression of a set of chemokine receptors potentially important for their peripheral tissue distribution in the skin. To further understand this process, I propose to dissect the TCR/ligand interaction-mediated fetal thymic selection process of gamma/delta T cells, in relationship with their unique homing properties and skin-specific tissue distribution and determine the positive selection associated CCR10 upregulation and CCR6 downregulation in sIEL development. These studies will help understand how immune cells go to different local tissues where they are positioned to fight against infection and tumor growth. This knowledge will be useful in helping to find a way to direct immune cells to specific tissues to treat different diseases.

Public Health Relevance

Tissue specific lymphocytes are important components of immune system and play an important role in the first line of defense against diseases. I propose here to study developmental mechanism of a class of skin-specific lymphocyte populations. These studies will help understand how immune cells go to different local tissues where they are positioned to fight against various diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI071043-05
Application #
8212563
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Miller, Lara R
Project Start
2008-02-15
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
5
Fiscal Year
2012
Total Cost
$301,260
Indirect Cost
$80,737
Name
Pennsylvania State University
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
Yang, Jie; Hu, Shaomin; Zhao, Luming et al. (2016) Selective programming of CCR10(+) innate lymphoid cells in skin-draining lymph nodes for cutaneous homeostatic regulation. Nat Immunol 17:48-56
Xiong, Na; Hu, Shaomin (2015) Regulation of intestinal IgA responses. Cell Mol Life Sci 72:2645-55
Xia, Mingcan; Hu, Shaomin; Fu, Yaoyao et al. (2014) CCR10 regulates balanced maintenance and function of resident regulatory and effector T cells to promote immune homeostasis in the skin. J Allergy Clin Immunol 134:634-644.e10
Hu, Shaomin; Xiong, Na (2013) Programmed downregulation of CCR6 is important for establishment of epidermal ýýýýT cells by regulating their thymic egress and epidermal location. J Immunol 190:3267-75
Xiong, Na; Fu, Yaoyao; Hu, Shaomin et al. (2012) CCR10 and its ligands in regulation of epithelial immunity and diseases. Protein Cell 3:571-80
Hu, Shaomin; Yang, KangKang; Yang, Jie et al. (2011) Critical roles of chemokine receptor CCR10 in regulating memory IgA responses in intestines. Proc Natl Acad Sci U S A 108:E1035-44
Xia, Mingcan; Qi, Qian; Jin, Yan et al. (2010) Differential roles of IL-2-inducible T cell kinase-mediated TCR signals in tissue-specific localization and maintenance of skin intraepithelial T cells. J Immunol 184:6807-14
Jin, Yan; Xia, Mingcan; Sun, Allen et al. (2010) CCR10 is important for the development of skin-specific gammadeltaT cells by regulating their migration and location. J Immunol 185:5723-31
Jin, Yan; Xia, Mingcan; Saylor, Christina M et al. (2010) Cutting edge: Intrinsic programming of thymic γδT cells for specific peripheral tissue localization. J Immunol 185:7156-60
Uche, Uzodinma N; Huber, Christopher R; Raulet, David H et al. (2009) Recombination signal sequence-associated restriction on TCRdelta gene rearrangement affects the development of tissue-specific gammadelta T cells. J Immunol 183:4931-9