The effects of B7‐dependent costimulation on T cell division and survival in vivo and in vitro are dependent on antigen concentration

• Published in: European journal of immunology 2003-08, Vol.33 (8), p.2074-2082
• Main Authors: Lumsden, Joanne M., Prasad, Simon J., Peach, Robert J., Ronchese, Franca
• Format: Article
• Language: English
• Subjects: Abatacept; Adoptive Transfer; Animals; Antigen presentation/processing; Antigens - administration & dosage; Antigens, CD - metabolism; B7-1 Antigen - metabolism; B7-2 Antigen; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; Cell Division - drug effects; Cell Survival - drug effects; Costimulation; Cytochrome c Group - immunology; Immunoconjugates - pharmacology; In Vitro Techniques; Lymphocyte Activation - drug effects; Membrane Glycoproteins - metabolism; Mice; Mice, Transgenic; Peptide Fragments - immunology; Receptors, Antigen, T-Cell - genetics; Recombinant Fusion Proteins - pharmacology; Thymidine - metabolism; T lymphocytes
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.200323929

We used 5‐(and 6‐) carboxyfluorescein diacetate succinimidyl ester labeled TCR‐transgenic CD4+ T cells to investigate the contribution of B7 costimulation to T cell activationand clonal expansion. B7 costimulation was blocked with the fusion protein cytotoxic T lymphocyte‐associated antigen‐4 (CTLA‐4)‐Ig, which prevents the interaction of B7 with its receptor CD28 on T cells. CTLA4‐Ig had different effects depending on the density of antigen (Ag)/MHC ligands available by T cells. In the presence of CTLA4‐Ig, tenfold higher concentrations of Ag were required for T cells to undergo cell division in vitro. At high Ag concentrations, T cell division occurred at comparable rates whether in the presence or absence of CTLA4‐Ig; however, T cell survival and clonal expansion were strongly inhibited. Addition of IL‐2 restored T cell survival but not responsiveness to low doses of Ag. In vivo, B7 costimulation was similarly required for the survival of Ag‐specific T cells but not for cell division in response to high amounts of Ag. Thus, B7 costimulation regulates CD4+ T cell responses by promoting cell division in the presence of limiting amounts of Ag, and by protecting T cells from the onset of apoptosis.