News and Publications

Cytokines in T-Cell Tolerance

C.G. Romball, W.O. Weigle

Previous studies indicated that lipopolysaccharide, IL-1, and TNF- can interfere with the induction of tolerance to deaggregated human -globulin and thus convert a tolerogenic signal to an immunogenic signal. Furthermore, research revealed that tolerance in the model system we use is induced in both type 1 and type 2 subsets of CD4⁺ helper T cells (T_H1 and T_H2 cells, respectively). In support of the latter finding, the dose-response curves in the induction of tolerance for the production of T_H1- and T_H2-associated cytokines were identical. These 2 pieces of information are compatible with the suggestion that tolerance is induced at the precursor CD4⁺ T-cell level and that the lack of cytokine induction by deaggregated human -globulin prevents expansion of the T_H1 and T_H2 subsets.

The differential ability of lipopolysaccharide and IL-1 to interfere with tolerance induction supports the general notion that the expansion of these 2 subsets involves different cytokine pathways. It thus follows that B cells, IL-1, and IL-4 most likely are responsible for expansion of the T_H2 subset, whereas other cytokines are involved in expansion of the T_H1 subset. Although IL-12 injected along with deaggregated human -globulin did not interfere with the induction of tolerance in either T_H1 or T_H2 cells, IL-12 in concert with other cytokines could be responsible for expansion of T_H1 cells.

Fc Receptors in Tolerance Induction

K.J. Whitmer, C.G. Romball, W.O. Weigle

Mice deficient in FcR (loss of functional receptors FcRI and FcRIII) or FcRII were used to examine the role of Fc receptors in the induction of peripheral tolerance to human -globulin. Establishment of an unresponsive state at both the T- and B-cell levels occurred in both types of Fc receptor--deficient mice. T-cell tolerance is manifested by a reduction in the function of T helper cells in antigen-induced release of cytokines associated with type 1 and type 2 T helper cells and by decreased proliferation in response to antigen-specific stimulation. B-cell tolerance was established in both Fc receptor--deficient and normal mice; no antibodies specific for human -globulin could be detected in a model for antibody production that bypasses the need for antigen-specific T cells. Although the FcRII plays no role in the induction of tolerance, a 10-fold enhancement of antibody production to antigenic human -globulin in such mice supports the findings of others that FcRII is a potent downregulator of the immune response.

PUBLICATIONS

Blossom, S., Chu, E.B., Weigle, W.O., Gilbert, K.M. CD40 ligand expressed on B cells in the BXSB mouse model of systemic lupus erythematosus. J. Immunol. 159:4580, 1997.

Gilbert, K.M., Thoman, M.L., Bauche, K., Pham, T., Weigle, W.O. Transforming growth factor-ß1 induces antigen-specific unresponsiveness of T cells. Immunol. Invest. 26:459, 1997.

Homan, D., Tishon, A., Berger, D.P., Weigle, W.O., von Herrath, M.G., Oldstone, M.B.A. Evidence for an underlying CD4 helper and CD8 T-cell defect in B cell-deficient mice: Failure to clear persistent virus infection after adoptive immunotherapy with virus-specific memory cells from µMT/µMT mice. J. Virol., in press.

Weigle, W.O. Advances in basic concepts of autoimmune disease. Clin. Lab. Med. 17:329, 1997.

Weigle, W.O. Overview of the immune system. In: Comprehensive Toxicology. Vol. 5: Toxicology of the Immune System. Lawrence, D.A. (Vol. Ed.). Elsevier, New York, 1997, p. 17.

Weigle, W.O. Tolerance: Models. In: Encyclopedia of Immunology, 2nd ed. Roitt, I.M., Delves, P.J. (Eds.). Academic Press, San Diego, 1998, p. 2359.

Weigle, W.O., Romball, C.G. CD4⁺ T cell subsets in cytokines involved in peripheral tolerance. Immunol. Today 18:533, 1997.