Elimination of pathogen-infected cells requires their sequential recognition by cells in the innate and acquired immune systems. A unique category of T cells collectively referred to as 'innate T cells'kinetically bridge the innate and acquired immune responses. Interestingly, the activation of innate T cells can be restricted by the expression of MHC-like molecules or class Ib molecules. The ability of innate T cells to respond rapidly stems from their lack of dependence on clonal expansion, resulting from less discriminating receptor-ligand interactions. By comparison, classical MHC molecules restrict conventional CD4 and CD8 T cells in the acquired immune response, and they require 10-14 days to clonally expand to sufficient numbers due to highly specific receptor-ligand interactions. The experiments in this grant will characterize the novel class Ib molecule MR1 that is evolutionarily conserved in mammals and restricts the development of mucosal-associated invariant T cells or MAIT cells in a manner dependent upon the commensal flora and B cells. MAIT cells have several features consistent with their function as innate T cells including i) invariant T cell receptor alpha chains, ii) the ability to rapidly release cytokines, and iii) apparent recognition of an evolutionarily conserved ligand. However, the nature of the MR1 ligand is unknown as is the physiological role of MAIT cells. In this application we will test whether MAIT cells detect Mycobacterium tuberculosis-infected cells and are critical components of host resistance to this pathogen. In addition, we will elucidate the nature of the MR1 ligand, the pathway by which it is presented, and the crystal structure of a ligand/MR1 complex. Cellular, molecular and structural dissection of MR1 antigen presentation to MAIT cells will critically define the mechanism and importance of this pathway in protective immunity to bacteria.

Public Health Relevance

Mucosal immune responses provide a front line defense against infection. In this grant we will study how a unique subset of T cells associated with mucosal tissues potentially control early immunity to Mycobacterium tuberculosis. Our findings will define the mechanism of bacteria recognition by these mucosal T cells and their function in controlling disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046553-12
Application #
8459413
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2000-09-30
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
12
Fiscal Year
2013
Total Cost
$353,628
Indirect Cost
$120,978
Name
Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Gold, Marielle C; McLaren, James E; Reistetter, Joseph A et al. (2014) MR1-restricted MAIT cells display ligand discrimination and pathogen selectivity through distinct T cell receptor usage. J Exp Med 211:1601-10
Ussher, James E; Bilton, Matthew; Attwod, Emma et al. (2014) CD161++ CD8+ T cells, including the MAIT cell subset, are specifically activated by IL-12+IL-18 in a TCR-independent manner. Eur J Immunol 44:195-203
Reantragoon, Rangsima; Corbett, Alexandra J; Sakala, Isaac G et al. (2013) Antigen-loaded MR1 tetramers define T cell receptor heterogeneity in mucosal-associated invariant T cells. J Exp Med 210:2305-20
Mage, Michael G; Dolan, Michael A; Wang, Rui et al. (2013) A structural and molecular dynamics approach to understanding the peptide-receptive transition state of MHC-I molecules. Mol Immunol 55:123-5
Cosgrove, Cormac; Ussher, James E; Rauch, Andri et al. (2013) Early and nonreversible decrease of CD161++ /MAIT cells in HIV infection. Blood 121:951-61
Young, Mary H; U'Ren, Lance; Huang, Shouxiong et al. (2013) MAIT cell recognition of MR1 on bacterially infected and uninfected cells. PLoS One 8:e53789
McCoy 4th, William H; Wang, Xiaoli; Yokoyama, Wayne M et al. (2013) Cowpox virus employs a two-pronged strategy to outflank MHCI antigen presentation. Mol Immunol 55:156-8
Reantragoon, Rangsima; Kjer-Nielsen, Lars; Patel, Onisha et al. (2012) Structural insight into MR1-mediated recognition of the mucosal associated invariant T cell receptor. J Exp Med 209:761-74
Huang, Shouxiong; Martin, Emmanuel; Kim, Sojung et al. (2009) MR1 antigen presentation to mucosal-associated invariant T cells was highly conserved in evolution. Proc Natl Acad Sci U S A 106:8290-5
Huang, Shouxiong; Gilfillan, Susan; Kim, Sojung et al. (2008) MR1 uses an endocytic pathway to activate mucosal-associated invariant T cells. J Exp Med 205:1201-11

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