Role of co-stimulation in CD8+ T cell activation

• DOI: 10.1093/intimm/10.5.619
• Publication Date: 2002-07-26T22:35:13Z
• Authors: N Pardigon
• Keywords: MESH: Signal Transduction; Cytotoxicity, Immunologic; MESH: Mice, Transgenic; Molecular Sequence Data; T lymphocytes; MESH: Mice, Inbred BALB C; Receptors, Antigen, T-Cell; Down-Regulation; Mice, Transgenic; MESH: Amino Acid Sequence; CD8-Positive T-Lymphocytes; Lymphocyte Activation; MESH: H-2 Antigens; [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity; Models, Biological; MESH: Down-Regulation; Mice; 03 medical and health sciences; 0302 clinical medicine; CD28 Antigens; MESH: Mice, Inbred C57BL; Animals; MESH: Animals; MESH: Cytotoxicity, Immunologic; Amino Acid Sequence; MESH: Lymphocyte Activation; [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity; MESH: Mice; MESH: CD28 Antigens; MESH: Cytokines; Mice, Inbred BALB C; MESH: Molecular Sequence Data; MESH: Models, Biological; H-2 Antigens; MESH: Interleukin-2; MESH: Receptors, Antigen, T-Cell; co-stimulatory molecules; MESH: CD8-Positive T-Lymphocytes; 3. Good health; Mice, Inbred C57BL; MESH: Oligopeptides; Cytokines; Interleukin-2; MHC; Oligopeptides; Signal Transduction

The two-signal model states that activation of naive T cells requires a signal 1 stimulus through the TCR and a co-stimulatory signal 2. By contrast, signal 1 alone is sufficient for pre-activated T cells. Recently, however, it has been shown that under certain conditions T cells can bypass the requirement for co-stimulation. For example, CD28-deficient mice, when immunized with lymphocytic choriomeningitis virus, mount a vigorous cytotoxic T lymphocyte response and clear the virus. As a continuous effort to unravel the mechanisms of T cell activation, we previously reported activation of hybridoma T cells by recombinant single-chain MHC molecules in the absence of antigen-presenting cells. In such reconstitution experiments, since the signals delivered to the T cells are well controlled, the contribution of any known or unknown signals can be ruled out. In the present study, we analyzed the requirements for activation of naive T cells by using splenocytes from TCR transgenic mice as a source of responding cells. We observed that naive CD8+ T cells are fully activated by signal 1 alone, but that co-stimulation lowers their activation threshold. Previously activated T cells are fully responsive, even when the first stimulation was performed in the absence of co-stimulation. They display a low activation threshold and are insensitive to co-stimulation. The physiological relevance of this finding and its consequences for immunotherapy as well as for our understanding of self-tolerance are discussed.