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ABSTRACT: Group 1 CD1 (CD1a, -b, and -c) presents self and foreign lipid antigens to multiple T-cell subsets in humans. However, in the absence of a suitable animal model, the specific functions and developmental requirements of these T cells remain unknown. To study group 1 CD1-restricted T cells in vivo, we generated double transgenic mice (HJ1Tg/hCD1Tg) that express group 1 CD1 molecules in a similar pattern to that observed in humans (hCD1Tg) as well as a TCR derived from a CD1b-autoreactive T-cell line (HJ1Tg). Using this model, we found that similar to CD1d-restricted NKT cells, HJ1 T cells exhibit an activated phenotype (CD44(hi)CD69(+)CD122(+)) and a subset of HJ1 T cells expresses NK1.1 and is selected by CD1b-expressing hematopoietic cells. HJ1 T cells secrete proinflammatory cytokines in response to stimulation with CD1b-expressing dendritic cells derived from humans as well as hCD1Tg mice, suggesting that they recognize species conserved self-lipid antigen(s). Importantly, this basal autoreactivity is enhanced by TLR-mediated signaling and HJ1 T cells can be activated and confer protection against Listeria infection. Taken together, our data indicate that CD1b-autoreactive T cells, unlike mycobacterial lipid antigen-specific T cells, are innate-like T cells that may contribute to early anti-microbial host defense.
Blood 08/2011; 118(14):3870-8. · 9.90 Impact Factor
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ABSTRACT: E26 Transformation specific (Ets) family transcription factors control the expression of a large number of genes regulating hematopoietic cell development and function. Two such transcription factors, Ets-1 and myeloid Elf-1-like factor (MEF), have been shown to play critical roles in both natural killer (NK)- and NKT-cell development, but not in the development of conventional T cells. In this study, we address the role of E74-like factor 1 (Elf-1), another Ets family transcription factor that is closely related to MEF but divergent from Ets-1, in NK- and NKT-cell development using Elf-1-deficient (Elf-1(-/-)) mice. Whereas the proportion of NK cells in Elf-1(-/-) mice was normal, the proportion of NKT cells was significantly reduced in the thymus and periphery of Elf-1(-/-) mice compared with wild-type (WT) mice. Although Ets-1-deficient mice lack NKT cells altogether, Elf-1(-/-) mice exhibited only a partial block in NKT-cell development caused by a cell-intrinsic defect in the selection, survival, and maturation of NKT cells. In addition, residual NKT cells found in Elf-1(-/-) mice produced less cytokine upon antigen stimulation compared with WT NKT cells. Our data demonstrate that Elf-1 plays an important and nonredundant role in the development and function of NKT cells, but is not involved in NK-cell development.
Blood 02/2011; 117(6):1880-7. · 9.90 Impact Factor
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ABSTRACT: Group 1 CD1 (CD1a, CD1b, and CD1c)-restricted T cells recognize mycobacterial lipid antigens and are found at higher frequencies in Mycobacterium tuberculosis (Mtb)-infected individuals. However, their role and dynamics during infection remain unknown because of the lack of a suitable small animal model. We have generated human group 1 CD1 transgenic (hCD1Tg) mice that express all three human group 1 CD1 isoforms and support the development of group 1 CD1-restricted T cells with diverse T cell receptor usage. Both mycobacterial infection and immunization with Mtb lipids elicit group 1 CD1-restricted Mtb lipid-specific T cell responses in hCD1Tg mice. In contrast to CD1d-restricted NKT cells, which rapidly respond to initial stimulation but exhibit anergy upon reexposure, group 1 CD1-restricted T cells exhibit delayed primary responses and more rapid secondary responses, similar to conventional T cells. Collectively, our data demonstrate that group 1 CD1-restricted T cells participate in adaptive immune responses upon mycobacterial infection and could serve as targets for the development of novel Mtb vaccines.
Journal of Experimental Medicine 10/2009; 206(11):2497-509. · 13.85 Impact Factor
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ABSTRACT: CD1a has a unique expression pattern among Ag-presenting molecules, expressed specifically on cortical thymocytes and APCs. As autoimmune disease, infection, and tumors can all result in alteration of CD1a expression, we are attempting to characterize the transcriptional regulation, and thus shed some light on specific expression, of CD1A. In this study, we have identified a minimal proximal promoter region required for CD1A transcription. Computer searches within this region identified numerous potential binding sites for lymphoid-specific transcription factors, including the ETS transcription factors, C/EBP, GATA, and CREB. Deletion and site-specific mutant analysis revealed a critical role of a potential cAMP response element (CRE) 965 bp upstream of the CD1A translation start site. Two activating transcription factor (ATF)/CREB family members, CREB-1 and ATF-2, are able to bind this site in vitro and in vivo. Notably, activation of ATF/CREB family members decreases CD1A transcription, while decrease in ATF-2 expression results in increased CD1A RNA level. The fact that these factors also bind the CD1A promoter in human monocytes strongly suggests a role for ATF/CREB family members in regulation of CD1A expression.
The Journal of Immunology 12/2006; 177(10):7024-32. · 5.79 Impact Factor
