T Helper Differentiation Proceeds Through Stat1-Dependent, Stat4-Dependent and Stat4-Independent Phases

Abstract

The effort to understand Th1 and Th2 development has included defining the specific signals that determine phenotype fate upon primary T cell activation by antigen. Numerous parameters of T cell activation appear to influence the overall balance of Th1/Th2 phenotype development, including the antigen presenting cells (APCs) used for T cell priming (Chang et al. 1990), antigen dose (Parish and Liew 1972; Hosken et al. 1995; Murray et al. 1992; Constant et al. 1995), antigen structure or particularly the affinity for the major histocompatibility complex (MHC) and T cell receptor (TCR) (Murray et al. 1992; Pfeiffer et al. 1991), levels of costimulation during T cell priming (Freeman et al. 1995; Lenschow et al. 1995; Kuchroo et al. 1995), genetic background (Murphy et al. 1994; Kubin et al. 1994), pathogen-derived materials, and cytokines present in the priming milieu (Le Gros et al. 1990; Swain et al. 1990, 1991; Sadick et al. 1990; Maggi et al. 1992; Manetti et al. 1993; Seder et al. 1993; Sypek et al. 1993; Chatelain et al. 1992; Belosevic et al. 1989; Hsieh et al. 1995; Howard 1986; Heinzel et al. 1989; Scott et al. 1988; Locksley and Scott 1991). While any of these parameters can alter the overall Th1/Th2 developmental balance, some appear to act directly to deliver final Thl/Th2 inducing signals to the T cell, while others appear to act indirectly, for example through modifying APC function, other innate immune cell activity, or the levels of Thl/Th2 inducing cytokines. The cytokines interleukin (IL)-12 and IL-4 act directly on receptors expressed by activated T cells, through specific STAT factors, to deliver direct differentiation-inducing signals (Kaplan et al. 1996a,b; Thierfelder et al. 1996). IL-4 activation of Stat6 is necessary for IL-4-induced Th2 phenotype development (Le Gros et al. 1990; Swain et al. 1990; Maggi et al. 1992; Chatelain et al. 1992; Kaplan et al. 1996a; Kopf et al. 1993; Kuhn et al. 1991; Betz and Fox 1990; Hou et al. 1994; Quelle et al. 1995; Shimoda et al. 1996; Takeda et al. 1996), and IL-12 activation of Stat4 is necessary for Th1 development (Kaplan et al. 1996b; Thierfelder et al. 1996; Jacobson et al. 1995; Bacon et al. 1995; Mattner et al. 1996; Magram et al. 1996; Szabo et al. 1995). While the molecular downstream targets of Stat6 and Stat4 for Th1/Th2 development are currently unknown, at present these two factors are the most proximal known signals controlling phenotype. It is unresolved at present through what mechanisms non-cytokine parameters influence Th1/Th2 balance, although it is likely that some may act by altering the initial levels of IL-4, IL-12 or interferon (IFN)-γ available to T cells during primary activation. Whether partial signaling through the TCR acts directly to induce Thl/Th2 developmental signals is an open issue at present. Changing antigen dose can cause apparent changes in phenotype development in vitro (Hosken et al. 1995). However, this effect was lost when IL-4 was neutralized, suggesting that cytokines are dominant in the hierarchy of these parameters.