Helper T‐Cell Subsets: Phenotype, Function and the Role of Lymphokines in Regulating their Development

Abstract

We have concentrated here on the lymphokines which might serve to regulate the different pathways of precursor development. We suggest that, as a result of antigenic stimulation, specific precursor cells both proliferate and become committed to develop into either an effector cell, a memory cell or an anergized cell. Anergy has not been dealt with in this review, but it is likely to be one of the options available. The development of an effector population takes 4-7 d (quite analogous to the time it takes for CTLp to become CTL and for resting B to become Ab-forming cells). The effector populations are large, generally IL-2R-positive cells. These cells have upregulated many adhesion molecule systems [e.g., Pgp-1, LFA-1 and ICAM-1 (Swain unpublished)], but downregulated the Mel-14 homing receptor. Effectors are ready to respond to APC such as specific B cells with a rapid synthesis and secretion of lymphokines. The effector population is then quickly downregulated, both by the turn off of lymphokine synthesis/secretion and possibly by its own suicide. This kind of pattern makes teleological sense since the cells making such high titers of lymphokines could have many potent pleitropic effects. It also seems to be the strategy employed in the generation of other terminally differentiated effectors (such as CTL and plasma cells). The requirement for restimulation and the requirement for direct and perhaps prolonged contact between the helper effector and the APC-B cell can be expected to help ensure that these lymphokines are localized (reviewed in Swain & Dutton 1987, Swain & Croft 1990) and effectively delivered to specific responding cells. We postulate that at the same time, or perhaps subsequent to this, another set of signals drives precursors to generate prememory cells. Our studies suggest these emerging memory cells may be phenotypically unique and we postulate that they are specialized to become a "long-lived" population of memory cells that will persist indefinitely as a protective population of increased frequency for the antigen encountered and which is also able to respond more rapidly and effectively. The greater effectiveness of the memory response would thus be due to dramatically increased frequency, to characteristic and stable changes in adhesion molecule expression and to the fact that, in addition to IL-2, resting memory cells also secrete at least low titers of IL-3, IL-4, IFN-gamma and other lymphokines upon initial restimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Amplification of T cells from human cord blood in serum-deprived culture stimulated with stem cell factor, interleukin-7 and interleukin-2

“…levels of IL-7 production occur in vivo. 36 On the other hand, although mouse models have demonstrated that IL-2 and IL-4 are dispensable for appropriate lymphoid development in vivo, 15,16 these growth factors that are produced mainly by specific T-cell subsets upon activation, 37,38 play important roles in regulating T-cell function in vitro.…”

Unique Ability of Activated CD4+ T Cells but Not Rested Effectors to Migrate to Non-lymphoid Sites in the Absence of Inflammation

“…3 We refer to the donor cells remaining 3 weeks or more after effector transfer as memory cells (16,17).…”

“…The combination of these signals leads to proliferation of naïve cells and begins the process of their differentiation to fully functional effectors capable of secreting high levels of cytokines and participating in helper and inflammatory reactions. The presence of polarizing cytokines such as IL-12 or IL-4 cause CD4 ϩ T cells to differentiate into Th1 or Th2 cells that produce distinct cytokine patterns and mediate different types of protective responses (3,4). Effector CD4 ϩ T cells are also characterized phenotypically by a decrease in the expression of CD62L and a concomitant increase in CD44 expression.…”

TID1, a mammalian homologue of the drosophila tumor suppressor lethal(2) tumorous imaginal discs, regulates activation-induced cell death in Th2 cells

“…Th1 cells, which characteristically produce IFN-g, are derived by culturing CD4 T cells with antigen in the presence of IL-12, while Th2 cells that characteristically produce IL-4, IL-5 and IL-13 are derived by culturing CD4 T cells with antigen in the presence of IL-4 (Swain et al, 1991;O'Garra and Murphy, 1994;Seder and Paul, 1994). Upon activation, Th1 cell lines undergo AICD within 12-48 h, while Th2 cell lines are significantly more resistant (Varadhachary et al, 1997;Zhang et al, 1997;Carter et al, 1998).…”