Control of Memory CD4 T Cell Recall by the CD28/B7 Costimulatory Pathway

• Published in: Journal of Immunology 2006-12, Vol.177 (11), p.7698-7706
• Main Authors: Ndejembi, Modesta P, Teijaro, John R, Patke, Deepa S, Bingaman, Adam W, Chandok, Meena R, Azimzadeh, Agnes, Nadler, Steven G, Farber, Donna L
• Format: Article
• Language: English
• Subjects: Abatacept; Animals; B7-1 Antigen - drug effects; B7-1 Antigen - immunology; CD28 Antigens - drug effects; CD28 Antigens - immunology; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; Hemagglutinin Glycoproteins, Influenza Virus - immunology; Immunoconjugates - pharmacology; Immunologic Memory; Immunosuppressive Agents - pharmacology; Influenza virus; Interferon-gamma - biosynthesis; Interferon-gamma - drug effects; Interleukin-2 - biosynthesis; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Mice; Mice, Inbred BALB C; Ovalbumin - immunology
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.177.11.7698

The CD28/B7 costimulatory pathway is generally considered dispensable for memory T cell responses, largely based on in vitro studies demonstrating memory T cell activation in the absence of CD28 engagement by B7 ligands. However, the susceptibility of memory CD4 T cells, including central (CD62L(high)) and effector memory (T(EM); CD62L(low)) subsets, to inhibition of CD28-derived costimulation has not been closely examined. In this study, we demonstrate that inhibition of CD28/B7 costimulation with the B7-binding fusion molecule CTLA4Ig has profound and specific effects on secondary responses mediated by memory CD4 T cells generated by priming with Ag or infection with influenza virus. In vitro, CTLA4Ig substantially inhibits IL-2, but not IFN-gamma production from heterogeneous memory CD4 T cells specific for influenza hemagglutinin or OVA in response to peptide challenge. Moreover, IL-2 production from polyclonal influenza-specific memory CD4 T cells in response to virus challenge was completely abrogated by CTLA4Ig with IFN-gamma production partially inhibited. When administered in vivo, CTLA4Ig significantly blocks Ag-driven memory CD4 T cell proliferation and expansion, without affecting early recall and activation. Importantly, CTLA4Ig treatment in vivo induced a striking shift in the phenotype of the responding population from predominantly T(EM) in control-treated mice to predominantly central memory T cells in CTLA4Ig-treated mice, suggesting biased effects of CTLA4Ig on T(EM) responses. Our results identify a novel role for CD28/B7 as a regulator of memory T cell responses, and have important clinical implications for using CTLA4Ig to abrogate the pathologic consequences of T(EM) cells in autoimmunity and chronic disease.