Activation of CD4+ T lymphocytes form interleukin 2-deficient mice by costimulatory B7 molecules.

Abstract

Interleukin 2 (IL-2)-deficient (IL-2-/-) mice develop hemolytic anemia and chronic inflammatory bowel disease. Importantly, the induction of disease in IL-2-deficient mice is critically dependent on CD4+ T cells. We have studied the requirements of T cells from IL-2-deficient mice for costimulation with B7 antigens. Stable B7-1 or B7-2 chinese hamster ovary (CHO) cell transfectants could synergize with anti-CD3 monoclonal antibody (mAb) to induce the proliferation of CD4+ T cells from IL-2-/-mutant mice.Further mechanistic studies established that B7-induced activation resulted in surface expression of the ca chain of the IL-2 receptor. B7-induced proliferation occurred independently of IL-4 and was largely independent of the common y chain of the IL-2, IL-4, Activation of primary T lymphocytes depends on costimulatory molecules that are typically provided by the antigenpresenting cell. The most potent costimulatory molecules known to date are the B7 proteins. The B7 subfamily of the immunoglobulin superfamily includes 45-to 60-kDa cellsurface glycoproteins that bind to two receptors on the T-cell surface, (1, 2). Two members of the B7 family, B7-1 (CD80) (3-5) and B7-2 (CD86) (6)(7)(8), have been cloned, and a third member, B7-3, has been postulated (9). In the case of CD4+ T lymphocytes, transfected cell lines that express B7-1 or B7-2 as well as B7-Ig fusion proteins can synergize with anti-CD3-, lectin-, or antigen-stimulated T-cell activation (6)(7)(8)(10)(11)(12)(13)(14)(15). Engagement of the CD28 receptor by B7 molecules results in the production of cytokines such as interleukin 2 (IL-2) (10) and interleukin 4 (IL-4) (13), in the cell-surface expression of cytokine receptors (15)

Prolonged TCR/CD28 Engagement Drives IL-2-Independent T Cell Clonal Expansion through Signaling Mediated by the Mammalian Target of Rapamycin

“…However, primary T cells also benefited from the synergy of CD3-, CD28-, and IL-2-driven proliferation and showed a comparable sensitivity to PI3K and mTOR inhibition. Thus, together our data support the idea that clonal expansion in vivo is independently determined by the TCR/CD28 engagement and by IL-2 (15)(16)(17) and possibly shaped by several additional factors. These factors include the persistence of Ag, the local autocrine and paracrine growth factor production, and the presence of additional costimulatory signals that are able to overcome the requirement for prolonged TCR/CD28-or IL-2-driven signals.…”

“…Studies performed in vivo in IL-2-, CD28-, and CTLA-4-deficient mice later supported the existence of IL-2-independent T cell expansion and a possible direct role for the TCR and CD28 in cell division. Indeed, T cells derived from IL-2-deficient mice showed proliferative responses that, although reduced, were sensitive to CD28-mediated costimulation (15)(16)(17) and restored by the addition of exogenous IL-2 (18). In contrast, T cells derived from CD28-deficient mice had severely impaired proliferative responses, only partially increased by the addition of exogenous IL-2 (19).…”

Broad Programming by IL-2 Receptor Signaling for Extended Growth to Multiple Cytokines and Functional Maturation of Antigen-Activated T Cells

“…This result typically has been suggested to reflect the inefficiency of the Abs, due to the high-affinity interaction of IL-2 with its receptor. Alternatively, such findings might represent IL-2-independent T cell growth, and several recent studies support this notion (15)(16)(17). In any case, the dynamics of T cell activation and the typical experimental systems in use do not allow clear separation of the outcome of TCR and costimulatory T cell activation vs IL-2-dependent effects.…”

Alternative Antigen Receptor (TCR) Signaling in T Cells Derived from ZAP-70-deficient Patients Expressing High Levels of Syk

“…It was therefore not surprising to observe a decreased level of CD3-induced IL-2 secretion in the Syk hi /ZAP-70 Ϫ T cells described here. The importance of IL-2 production in T cell mitogenesis is underscored by the finding that CD3-induced proliferation is severely impaired in murine and human T cells that cannot secrete IL-2 as a result of mutations in the IL-2 gene (35)(36)(37). However, in contrast with these IL-2-deficient cells in which CD3-induced proliferation increases to normal levels in the presence of recombinant IL-2, the profound proliferation defect in CD3-induced Syk hi /ZAP-70 Ϫ T cells could not be alleviated by the addition of exogenous IL-2.…”