An antigen receptor-driven, interleukin 2-independent pathway for proliferation of murine cytolytic T lymphocyte clones.

Abstract

Proliferation of T lymphocytes can be induced by IL-2, either through an autocrine pathway in which the responding cell produces its own IL-2 or through an exocrine pathway in which IL-2 secreted by Th stimulates proliferation of IL-2-dependent CTL. However, proliferation of at least some CTL clones, such as CTL L3 and CTL dB45, also can be induced by stimulation of the antigen receptor in the absence of IL-2. Stimulation of these cloned CTL with T cell-depleted allogeneic spleen cells, allogeneic tumor cells, or immobilized mAb reactive with the T cell antigen receptor (TCR) induced thymidine incorporation, entry into cell cycle, and secretion of macrophage activating factor, but these stimuli did not induce the secretion of IL-2. Several observations indicated that such proliferation of cloned CTL induced by stimulation of the TCR was independent of IL-2; IL-2 could not be detected in supernatants from stimulated CTL cells. mAbs reactive with the murine IL-2-R efficiently blocked IL-2-mediated thymidine incorporation in cloned CTL and Th, but had no inhibitory effect on TCR-driven thymidine incorporation in the CTL clones. TCR-driven thymidine incorporation in cloned Th L2 cells was profoundly inhibited by these antibodies, indicating the operation of an IL-2-mediated autocrine pathway for proliferation in this cloned Th. When antibodies to the TCR were used to stimulate cloned CTL and Th, IFN-gamma mRNA was easily shown in the cloned CTL and Th. Although IL-2 mRNA could be detected in the cloned Th, it was never observed in the cloned CTL. These findings provide evidence for the existence of a TCR-mediated, IL-2-independent pathway for induction of cellular proliferation in cloned murine CTL.

Different Roles for L3T4+ and Lyt 2+ T Cell Subsets in the Control of an Acute Herpes Simplex Virus Infection of the Skin and Nervous System

“…The dogma on the induction of Lyt 2 cytotoxic T cell responses in vitro clearly implicates L3T4 (Lyt 1) helper cells as providing the necessary signals for activating cytotoxic T lymphocyte precursors to their aggressor status (Cantor & Boyse, 1975;Wagner & Rollinghoff, 1978). Other groups have demonstrated departures from this dogma and have suggested that Lyt 2 cells provide their own source of 'helper' factors, or else receive induction signals from other cells (Andrus et al, 1981 ;Mizuochi et al, 1985;Moldwin et al, 1986;Sprent & Schaefer, 1986). Whatever the mechanism involved in Lyt 2 cell activation, it is clear that a deficiency in L3T4 cells actually leads to an augmented cytotoxic T cell response to this virus.…”

Suppressive Oligodeoxynucleotides Inhibit Th1 Differentiation by Blocking IFN-γ- and IL-12-Mediated Signaling

“…IFN-␥ gene expression during CD4 ϩ T cell activation is mediated by signals transduced through the TCR, IL-12R, and/or IFN-␥R (20,36,37). Th1 maturation involves IFN-␥-mediated phosphorylation of STAT1, which in turn up-regulates expression of the T-bet transcription factor (38,39).…”

Cytokine‐Independent Proliferation of IL‐2‐Nonproducing CTL Clones in Association with High TCR‐Signal Transduction Responses

“…A costimulatory signal was not always required for induction of T cell proliferation in response to TCR stimulation, as shown in this study and others (6,10). However, it has not been clarified why some T cells were proliferative in response to the CD3-dependent signal alone.…”

“…Although some CTLs produce IL-2, most other CTLs that do not produce IL-2 require exogeneous IL-2 for proliferation. However, some CTL clones were shown to proliferate in response to antigenic cells, anti-CD3 monoclonal antibodies (aCD3) (10) or phorbolester 12-myristate 13-acetate (PMA) (6) without production of IL-2. It has not been clarified why these CTLs proliferate in response to TCR stimulation independently of costimulatory cells or IL-2.…”