Role of co-stimulation in CD8+ T cell activation.
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.
Pardigon
N
N
Unité de Biologie Moléculaire du Gène, INSERM U277, Institut Pasteur, Paris, France.
Bercovici
N
N
Calbo
S
S
Santos-Lima
E C
EC
Liblau
R
R
Kourilsky
P
P
Abastado
J P
JP
D000595:Amino Acid Sequence; D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D015536:Down-Regulation; D006183:H-2 Antigens / Q000378:metabolism; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D015398:Signal Transduction
D018106:CD28 Antigens; D016207:Cytokines; D006183:H-2 Antigens; D007376:Interleukin-2; D009842:Oligopeptides; D011948:Receptors, Antigen, T-Cell