Analysis of T cell function in autoimmune murine strains. Defects in production and responsiveness to interleukin 2.

Abstract

In the studies reported here, we have analyzed the production and consumption of T cell growth factor, more recently termed interleukin 2 (IL-2), as well as some cell-mediated immune functions, in murine strains [MRL, BXSB, NZB, and (NZB x NZWF1] manifesting systemic lupus erythematosus (SLE)-like syndromes. Young (4-6 wk) or old (4-8 mo) autoimmune or normal mice were studied and compared with regard to the following T cell functions in vitro after stimulation with concanavalin A (Con A): (a) mitogenic response; (b) IL-2 levels in culture supernates; and (c) the ability to respond to and adsorb IL-2. In addition, proliferative activity in the allogeneic mixed leukocyte culture and frequency of alloreactive cytotoxic T lymphocyte precursors (CTLp) were analyzed in some of these strains. Reduced Con A-induced mitogenic responses and IL-2 production appeared at 3-6 wk of age in the early, severe SLE developing strains MRL-Mp-lpr/lpr (MRL/l) and male BXSB and progressed thereafter. Similar defects appeared at a later stage in MRL/Mp-+/+ and (NZB x NZW)F1 hybrid mice, which develop late disease. Detailed analysis of cells from the enlarged lymph nodes and spleens of older MRL/l mice demonstrated that such cells: (a) responded poorly to Con A or allogeneic stimulator cells, even in the presence of exogenous IL-2; (b) did not suppress IL-2 production by normal spleen cells; (c) were relatively incapable of adsorbing or inactivating IL-2; and (d) had a markedly reduced anti-H-2b CTLp frequency in the mesenteric lymph nodes but a normal one in spleen. These results indicate that the proliferating Thy-1.2+, Lyt-1+ T cells in MRL/l mice are defective in their responses to mitogenic stimuli, in IL-2 production, and in expression of acceptor sites for IL-2. The relevance of these defects to the MRL/l disease as well as to the role of IL-2 in autoimmunity in general remains to be determined.

A peptide derived from an autoantibody can stimulate t cells in the (nzb × nzw)f1 mouse model of systemic lupus erythematosus

“…Loss of the response was expected, however, since NZBW mice are known to develop defective T cell proliferation to antigens and mitogens as they age (22,23). Our data suggest that mice of this strain have at an early age a T cell repertoire that can be activated by several peptides derived from A6.1 Ig.…”

“…Diminished ability of T cells to proliferate as NZB/W mice (and other murine lupus models) age has been reported by several investigators (22)(23)(24)(25). This fact was documented in experiments done in our system (data not shown).…”

Immunological mechanisms and clinical implications of regulatory T cell deficiency in a systemic autoimmune disorder: Roles of IL‐2 versus IL‐15

“…The broad autoreactivity is known to be predominately T cell dependent [2], but the immunological mechanism underlying such a systemic loss of self tolerance is not fully understood. In contrast to B cell hyperactivity [3], reduced IL-2 production and hyporesponsiveness of T cells are characteristic of SLE [4,5]. Moreover, impaired cellular immunity, complement deficiency, defects in the clearance of dying cells by macrophages [6][7][8], and the disrupted mechanisms of tolerance induction [9][10][11] are among many immunological characteristics of, or potential mechanisms proposed for, the disease.…”

Immuno- and genetic therapy in autoimmune diseases

“…71 The ability of T cells in MRL/lpr to cap, proliferate, express IL-2 surface receptors and produce IL-2 after antigenic or mitogenic stimulation is impaired. 72 Some studies suggest that this may be due to deficient signalling via the phosphoinositide pathway. 73 Furthermore, studies suggest that the T cells are unable to cause activated B lymphocyte apoptosis due to a failure to signal through the mutated Fas gene in B cells.…”