T-bet-dependent regulation of CD8+ T-cell expansion during experimental Trypanosoma cruzi infection.
The transcription factor T-bet (T-box, expressed in T cells), promotes type I immunity to pathogens through effects involving T cells and dendritic cells. In CD8(+) T cells, many of the functions of T-bet are redundant with those of eomesodermin (Eomes), a paralogue of T-bet. We therefore investigated the role of T-bet in immunity to Trypanosoma cruzi, an intracellular pathogen that causes Chagas disease, and which requires CD8(+) T cells for resistance. T-bet-deficient mice (tbx21(-/-)) were highly susceptible to T. cruzi infection, marked by severe liver pathology. CD8(+) T cells from infected tbx21(-/-) mice expressed typical markers of activation, including CD44 and CD25. In striking contrast, there was a 10-fold reduction in the number of antigen-specific CD8(+) T cells in tbx21(-/-) mice. This reduction was not a consequence of increased apoptosis or altered tissue-specific migration. Further, antigen-presenting cell (APC) functions in tbx21(-/-) mice were normal as we observed comparable levels of B7-1, B7-2 and CD40 expression as well as normal antigen-driven proliferation of wild-type CD8(+) T cells in infected tbx21(-/-) mice. However, adoptive transfer of naïve T cells from tbx21(-/-) donors into infected Rag-2-deficient mice (tbx21(+/+)) demonstrated a similar quantitative defect in CD8(+) T-cell expansion. These data demonstrate that T-bet facilitates immunity to T. cruzi by promoting the expansion of T. cruzi-specific CD8(+) T cells in a T cell-intrinsic manner. They also serve to further illustrate the multifaceted functions of T-box proteins in regulating quantitative aspects of T-cell immunity, in addition to qualitative components such as cytokine production.
Cobb
Dustin
D
Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA.
Guo
Siqi
S
Lara
Ana M
AM
Manque
Patricio
P
Buck
Gregory
G
Smeltz
Ronald B
RB
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D014355:Chagas Disease / Q000276:immunology* / Q000517:prevention & control; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D007111:Immunity, Cellular; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013154:Spleen / Q000276:immunology; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000276:immunology*; D000098815:T-bet Transcription Factor
D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor