IL-4 signaling, gene transcription regulation, and the control of effector T cells.

The central goal of our laboratory is to understand the regulation of lymphoid cells through molecular mechanisms of signal transduction and transcriptional control. A long-standing focus has been on changes that influence the effector function of mature lymphocytes. Work in the laboratory is oriented toward the identification of new regulatory mechanisms using cell lines and primary cells, and the validation of these in vitro findings in mouse models of immune responses and diseases. In this review, we summarize key insights into the regulation of T helper cell function during the phase of immunity where effector responses arise de novo. Particular interest has been centered on cytokine gene regulation as part of T cell differentiation into the Th1 and Th2 subsets. Information on IL-4 receptor signaling and the role of NF-kappaB transcription factors is reviewed. Our more recent work is designed to understand how regulation at the Th1/2 effector stages is related to the control of memory T cell survival, immune recall responses, and the role of these responses in immune-mediated disease.

IL-4-dependent induction of BCL-2 and BCL-X(L)IN activated T lymphocytes through a STAT6- and pi 3-kinase-independent pathway.

Both B and T lymphocytes require ongoing signals to maintain their viability. The pleiotropic cytokine interleukin (IL-) 4 plays an important role in the maintenance of activated T cells, perhaps reflecting induction of the anti-apoptotic genes Bcl-2 and Bcl-X(L). However, it is not known which of the signalling pathways known to link the IL-4 receptor with transcription regulation are required, or if the levels of Bcl-2/X induction under such physiologic conditions are sufficient to account for the anti-apoptotic effects of IL-4. We report here that although blockade of pathways (PI 3-kinase and pp70 S6 kinase) recruited by the IRS-1/2 adaptor proteins inhibited the anti-apoptotic function of IL-4, Bcl-2/X induction were normal. These findings were recapitulated in primary and culture-adapted T cells whose Stat6 signalling pathway also was defective. These results demonstrate that both the Stat6 and PI 3-kinase pathways can be dispensable for Bcl-2/X induction by IL-4, thus suggesting the involvement of an additional signal transduction pathway. Moreover, the preservation of Bcl-2/X induction despite inhibition of the anti-apoptotic function of IL-4 indicates that this cytokine activates additional protective mechanisms.

Preferential role for NF-kappa B/Rel signaling in the type 1 but not type 2 T cell-dependent immune response in vivo.

T cell function is a critical determinant of immune responses as well as susceptibility to allergic diseases. Activated T cells can differentiate into effectors whose cytokine profile is limited to type 1 (IFN-gamma-dominant) or type 2 (IL-4-, IL-5-dominant) patterns. To investigate mechanisms that connect extracellular stimuli with the regulation of effector T cell function, we have measured immune responses of transgenic mice whose NF-kappa B/Rel signaling pathway is inhibited in T cells. Surprisingly, these mice developed type 2 T cell-dependent responses (IgE and eosinophil recruitment) in a model of allergic pulmonary inflammation. In contrast, type 1 T cell responses were severely impaired, as evidenced by markedly diminished delayed-type hypersensitivity responses, IFN-gamma production, and Ag-specific IgG2a levels. Taken together, these data indicate that inhibition of NF-kappa B can lead to preferential impairment of type 1 as compared with type 2 T cell-dependent responses.

In vivo function of an interleukin 2 receptor beta chain (IL-2Rbeta)/IL-4Ralpha cytokine receptor chimera potentiates allergic airway disease.

Strength of T cell receptor (TCR) signaling, coreceptors, costimulation, antigen-presenting cell type, and cytokines all play crucial roles in determining the efficiency with which type 2 T lymphocytes (Th2, Tc2) develop from uncommitted precursors. To investigate in vivo regulatory mechanisms that control the population of type 2 T cells and disease susceptibility, we have created lines of transgenic mice in which expression of a chimeric cytokine receptor (the mouse interleukin 2 receptor beta chain [IL-2Rbeta] extracellular domain fused to the cytoplasmic tail of IL-4Ralpha) is targeted to the T lymphoid lineage using the proximal lck promoter. This chimera transduced IL-4-specific signals in response to IL-2 binding and dramatically enhanced type 2 responses (IL-4, IL-5, and immunoglobulin E production) upon in vitro TCR stimulation or in vivo antigen challenge. Thus, type 2 effector function was augmented by IL-4 signals transduced through a chimeric receptor expressed in a T cell-specific manner. This influence was sufficient for establishment of antigen-induced allergic airway hyperresponsiveness on a disease-resistant background (C57BL/6).