ELSEVIER zyxwvutsrqpo Influence of CD26 and Integrins on the Antigen Sensitivity of Human Memory T Cells Fiorenza Falcioni, Chikao Morimoto, Zoltan A. Nag-y Himanshu Shah, Damir VidoviC, Charles Belunis, David Bolin, and ABSTRACT: The antigen sensitivity of class II MHC- restricted human CD4 T-cell clones is demonstrated to increase gradually with time after restimulation. This is manifested in a requirement of less antigen in culture, as well as decreased numbers of peptide-MHC complexes per APC for T-cell activation, and in an increased resistance to inhibition by class II MHC blockade. The increase in antigen sensitivity is accompanied by increased cell- surface expression of ~~26, LFA-1, and VLA-1, whereas the expression of TCR and a series of other cell-surface molecules remains unchanged. Using appropriate mono- ABBREVIATIONS APC antigen-presenting cell EBV Epstein-Barr virus FACS fluorescence-activated cell sorter HA influenza virus hemagglutinin HPLC high performance liquid chromatography IFN interferon Ig immunoglobulin IL interleukin I/S inhibitor stimulator ratio LFA leukocyte functional antigen mAb monoclonal antibody INTRODUCTION The activation of T cells requires recognition of peptide- major histocompatibility complex (MHC) complexes on antigen-presenting cells (APC) by T-cell antigen recep- From the Department of InfammationlAutoimmune Diseases, Hoffmann- La Roche, Inc., Nut&, New Jersey, USA (F. F., H.S., D. V., C. B., D. B., Z.A.N.), and the Division of Tumor Immunology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA (C. M.). Address reprint requests to Dr. Z. A. Nagy, Department of lnfamma- tionlAutoimmune Diseases, Hoff&m-La Roche, Inc. ( Building 86lRoom 6020. 340 Kingsland Street, Nut&, NJ 0711 O-l 199. USA. Received January 10, 1996; accepted April 24, 1996. clonal antibodies, we have shown that ~~26 and LFA-1 contribute directly to the increased antigen sensitivity of “late-stage” T-cell clones. The late-memory T-cell phe- notype established in this study is shown to occur also among T cells activated in uiuo. We suggest that increas- ing the antigen sensitivity via antigen-nonspecific mol- ecules is a physiologic mechanism for maintaining T-cell memory in face of decreasing antigen concentration, and for ensuring preferential activation of memory T cells upon repeated encounter with antigen. Human Immunology 50, 79-90 (1996) MHC MLR PBL PCR PHA PP SD,, TCR Th TT VLA major histocompatibility complex mixed lymphocyte reaction peripheral blood lymphocyte polymerase chain reaction phytohemagglutinin pertussis toxin peptide half-maximal stimulatory dose T-cell antigen receptor T helper tetanus toxoid very late activation antigen tots (TCR), as well as a series of antigen-nonspecific molecular interactions between the two cells. The latter are mediated by pairs of molecules expressed on the sur- face of T cells and APC, respectively, collectively referred to as accessory molecules. Certain accessory molecules act as co-receptors for MHC recognition (CD4 and CD8 113); others facilitate cell-to-cell adhesion (integrins [2]); yet others provide signals that synergize with TCR-mediated activation (costimulatory molecules {3]). Antigen recog- nition in the absence of accessory molecular interactions results in T-cell nonresponsiveness (anergy 13, 41). Human Immunology 50, 79-90 (1996) 0 American Soc~ery for Histocompatibility and Immunogenetics, 1996 019%8859196/$15.00 PI1 SO198-8859(96)00121-S