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Immunology Research Division, Department of Pathology, Brigham & Women’s Hospital and Harvard Medical School, Boston MA 02115
The differentiation of CD4+ T cells into a Th1 vs Th2
phenotype profoundly influences the outcome of autoimmune and
infectious diseases. B7 costimulation has been shown to affect the
production of both Th1 and Th2 cytokines, depending on the system
studied. There is, consequently, great interest in manipulating the B7
costimulatory signal for therapeutic purposes. To optimally manipulate
this key immunoregulatory pathway, the contribution of B7 costimulation
to cytokine production requires further clarification. We have compared
the B7 requirement for cytokine production by naive vs previously
activated T cells using DO11.10 TCR transgenic CD4+ T cells
and splenic APCs from mice lacking B7 expression. Our data indicate
that induction of IL-4 production and Th2 differentiation by naive T
cells is highly dependent on B7 molecules, whereas IL-4 production by
previously activated T cells is B7 independent. The predominant
contribution of B7-mediated signals to Th1 cytokine production by both
naive and primed T cells is upon IL-2 production (and expansion) rather
than IFN-
(effector cytokine) production. Thus, our studies
demonstrate that the antigenic experience of a T cell at the time of B7
blockade may determine whether blockade predominantly affects T cell
expansion, differentiation, or effector cytokine production. These
differential effects of B7 costimulation on IL-2 vs IFN- production
and on IL-4 production by naive vs primed T cells have important
implications for understanding how B7:CD28/CTLA4 blockade can be
effectively used to manipulate cytokine production in
vivo.
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S. A. Jenks and J. Miller Inhibition of IL-4 Responses After T Cell Priming in the Context of LFA-1 Costimulation Is Not Reversed by Restimulation in the Presence of CD28 Costimulation J. Immunol., January 1, 2000; 164(1): 72 - 78. [Abstract] [Full Text] [PDF]
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J. T. Chang, B. M. Segal, and E. M. Shevach Role of Costimulation in the Induction of the IL-12/IL-12 Receptor Pathway and the Development of Autoimmunity J. Immunol., January 1, 2000; 164(1): 100 - 106. [Abstract] [Full Text] [PDF]
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H.-W. Mittrucker, A. Kohler, T. W. Mak, and S. H. E. Kaufmann Critical Role of CD28 in Protective Immunity Against Salmonella typhimurium J. Immunol., December 15, 1999; 163(12): 6769 - 6776. [Abstract] [Full Text] [PDF]
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E. Israel-Assayag, M. Fournier, and Y. Cormier Blockade of T Cell Costimulation by CTLA4-Ig Inhibits Lung Inflammation in Murine Hypersensitivity Pneumonitis J. Immunol., December 15, 1999; 163(12): 6794 - 6799. [Abstract] [Full Text] [PDF]
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A. N. Schweitzer and A. H. Sharpe Mutual Regulation Between B7-1 (CD80) Expressed on T Cells and IL-4 J. Immunol., November 1, 1999; 163(9): 4819 - 4825. [Abstract] [Full Text] [PDF]
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A. J. Coyle, C. Lloyd, J. Tian, T. Nguyen, C. Erikkson, L. Wang, P. Ottoson, P. Persson, T. Delaney, S. Lehar, et al. Crucial Role of the Interleukin 1 Receptor Family Member T1/ST2 in T Helper Cell Type 2–mediated Lung Mucosal Immune Responses J. Exp. Med., October 4, 1999; 190(7): 895 - 902. [Abstract] [Full Text] [PDF]
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E. N. Villegas, M. M. Elloso, G. Reichmann, R. Peach, and C. A. Hunter Role of CD28 in the Generation of Effector and Memory Responses Required for Resistance to Toxoplasma gondii J. Immunol., September 15, 1999; 163(6): 3344 - 3353. [Abstract] [Full Text] [PDF]
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T. T. Chang, C. Jabs, R. A. Sobel, V. K. Kuchroo, and A. H. Sharpe Studies in B7-deficient Mice Reveal a Critical Role for B7 Costimulation in Both Induction and Effector Phases of Experimental Autoimmune Encephalomyelitis J. Exp. Med., September 6, 1999; 190(5): 733 - 740. [Abstract] [Full Text] [PDF]
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M. A. Oosterwegel, D. A. Mandelbrot, S. D. Boyd, R. B. Lorsbach, D. Y. Jarrett, A. K. Abbas, and A. H. Sharpe The Role of CTLA-4 in Regulating Th2 Differentiation J. Immunol., September 1, 1999; 163(5): 2634 - 2639. [Abstract] [Full Text] [PDF]
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M. D. Denton, C. S. Geehan, S. I. Alexander, M. H. Sayegh, and D. M. Briscoe Endothelial Cells Modify the Costimulatory Capacity of Transmigrating Leukocytes and Promote CD28-mediated CD4+ T Cell Alloactivation J. Exp. Med., August 16, 1999; 190(4): 555 - 566. [Abstract] [Full Text] [PDF]
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 S. E Burastero and G. A Rossi Immunomodulation by interference with co-stimulatory molecules: therapeutic perspectives in asthma Thorax, June 1, 1999; 54(6): 554 - 557. [Full Text]
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H. Gudmundsdottir, A. D. Wells, and L. A. Turka Dynamics and Requirements of T Cell Clonal Expansion In Vivo at the Single-Cell Level: Effector Function Is Linked to Proliferative Capacity J. Immunol., May 1, 1999; 162(9): 5212 - 5223. [Abstract] [Full Text] [PDF]
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R. J. Greenwald, J. F. Urban, M. J. Ekkens, S.-J. Chen, D. Nguyen, H. Fang, F. D. Finkelman, A. H. Sharpe, and W. C. Gause B7-2 Is Required for the Progression But Not the Initiation of the Type 2 Immune Response to a Gastrointestinal Nematode Parasite J. Immunol., April 1, 1999; 162(7): 4133 - 4139. [Abstract] [Full Text] [PDF]
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H. J. Hernandez, A. H. Sharpe, and M. J. Stadecker Experimental Murine Schistosomiasis in the Absence of B7 Costimulatory Molecules: Reversal of Elicited T Cell Cytokine Profile and Partial Inhibition of Egg Granuloma Formation J. Immunol., March 1, 1999; 162(5): 2884 - 2889. [Abstract] [Full Text] [PDF]
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