Differential costimulatory effects of adhesion molecules B7, ICAM-1, LFA-3, and VCAM-1 on resting and antigen-primed CD4+ T lymphocytes.
Optimal proliferation of T cells although initiated via ligation of the CD3/TCR complex requires additional stimulation resulting from adhesive interactions between costimulatory receptors (R) on T cells and their counter-R on APC. At least four distinct adhesion molecules (counter-R) present on APC, B7, ICAM-1 (CD54), LFA-3 (CD58), and VCAM-1 have been individually shown to costimulate T cell activation. Because some of these molecules may be expressed simultaneously on APC, it has been difficult to examine relative contributions of individual counter-R during the induction of T cell proliferation. We have produced soluble IgC gamma 1 fusion chimeras (receptor globulins or Rg) of B7, ICAM-1, LFA-3, and VCAM-1 and compared their relative abilities to costimulate proliferation of resting or Ag-primed CD4+ T cells. When co-immobilized with mAb directed at TCR alpha beta or CD3 but not CD2 or CD28, each Rg induced proliferation of both resting and Ag-primed CD4+ cells. In contrast, similarly co-immobilized CD7 Rg or ELAM-1 Rg were ineffective. Resting CD4+ T cells produced more IL-2, expressed significantly higher levels of IL-2R alpha, and proliferated more efficiently when costimulated with either ICAM-1 Rg or VCAM-1 Rg than with B7 Rg or LFA-3 Rg. CD4+ CD45RO+ memory T cells proliferated more vigorously in response to the costimulation by each of the four Rg than CD4+ CD45RA+ naive T cells. In contrast with the behavior of resting CD4+ T cells, proliferation of Ag-preactivated CD4+ T cells was most efficient when costimulated by B7 Rg. The costimulatory effect of LFA-3 Rg on Ag-primed CD4+ T cells was weaker than that of B7 Rg but was significantly greater than that of either ICAM-1 Rg or VCAM-1 Rg. These results suggest that resting and Ag-primed CD4+ T cells preferentially respond by proliferation to different costimulatory counter-R. ICAM-1 and VCAM-1 may be involved in the initiation of proliferation of Ag-responsive T cells, and B7 and LFA-3 may facilitate sustained proliferation of Ag-primed T cells. The cumulative costimulation by the above counter-R may facilitate optimal expression of various regulatory and effector functions of T cells.
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121.
N K
NK
Damle
K
K
Klussman
P S
PS
Linsley
A
A
Aruffo
D015703:Antigens, CD / Q000032:analysis; D000954:Antigens, Surface / Q000502:physiology*; D018122:B7-1 Antigen; D001483:Base Sequence; D015704:CD4 Antigens / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018968:CD58 Antigens; D015815:Cell Adhesion Molecules / Q000502:physiology*; D002478:Cells, Cultured; D006649:Histocompatibility Antigens / Q000032:analysis; D006801:Humans; D018799:Intercellular Adhesion Molecule-1; D007376:Interleukin-2 / Q000096:biosynthesis; D017493:Leukocyte Common Antigens; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000502:physiology*; D008969:Molecular Sequence Data; D015375:Receptors, Interleukin-2 / Q000032:analysis; D019010:Vascular Cell Adhesion Molecule-1
D015703:Antigens, CD; D000954:Antigens, Surface; D018122:B7-1 Antigen; D015704:CD4 Antigens; D018968:CD58 Antigens; D015815:Cell Adhesion Molecules; D006649:Histocompatibility Antigens; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D015375:Receptors, Interleukin-2; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D017493:Leukocyte Common Antigens