Control of memory CD4 T cell recall by the CD28/B7 costimulatory pathway.
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.
Ndejembi
Modesta P
MP
Division of Transplantation, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA.
Teijaro
John R
JR
Patke
Deepa S
DS
Bingaman
Adam W
AW
Chandok
Meena R
MR
Azimzadeh
Agnes
A
Nadler
Steven G
SG
Farber
Donna L
DL
D000069594:Abatacept; D000818:Animals; D018122:B7-1 Antigen / Q000187:drug effects / Q000276:immunology*; D018106:CD28 Antigens / Q000187:drug effects / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology; D018796:Immunoconjugates / Q000494:pharmacology; D007156:Immunologic Memory; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000187:drug effects; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology
D018122:B7-1 Antigen; D018106:CD28 Antigens; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D000069594:Abatacept; D007371:Interferon-gamma; D010047:Ovalbumin