Roles of Adhesion Molecules in T‐Cell Recognition: Fundamental Similarities between Four Integrins on Resting Human T Cells (LFA‐1, VLA‐4, VLA‐5, VLA‐6) in Expression, Binding, and Costimulation

Abstract

This review summarizes our recent work on expression and function of 4 integrins on resting human CD4+ T cells. Three themes are highlighted: multiplicity of molecular pathways of adhesion, regulation of adhesion, and costimulation by adhesion molecules. Four distinct receptor/ligand interactions have been elucidated: LFA-1/ICAM-1, VLA-5/fibronection, VLA-4/fibronectin, and VLA-6/laminin. Our studies indicate fundamental similarities in function and regulation of these four receptor/ligand interactions: 1) acute activation of the T cell (by CD3/TCR crosslinking or by PMA) induces rapid but transient integrin binding function; and 2) higher expression of each integrin on memory T cells compared to naive T cells results in greater binding of memory cells to each ligand. The identification of T-cell integrins (VLA-4, VLA-5, VLA-6) which interact with ECM components directs attention to the potential importance of T-cell interactions with ECM components which either may be immobilized in ECM or which may act as molecular bridges between cells. The existence of multiple adhesion pathways, of multiple ligands for a single receptor (such as LFA-1/ICAM-1 and LFA-1/ICAM-2), multiple receptors for a single ligand (such as VLA-4/FN and VLA-5/FN), and regulation of ligand expression (ICAM-1) provides opportunities for co-operativity, rebundancy and diversity which the T cell utilizes to exquisitely regulate its adhesive interactions. The thesis that adhesion molecules can be multifunctional receptors that also influence signalling is demonstrated by our findings that each of these integrin receptor/ligand interactions is capable of providing a potent costimulatory signal to CD3-mediated T-cell activation. The importance of interactions of T-cell integrins with their cell surface and ECM ligands is discussed with respect to T-cell migration, differentiation and recognition. Analysis of the precise mechanisms by which T cells regulate and exploit these multiple receptor/ligand interactions and the resulting functional consequences of those interactions will be exciting areas of future research.

Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression.

“…I1.-10 and v-Ibl0 failed to modulate class I MHC expression on monocytes and did not affect the levels of CDlla, CD11b, CDllc, CD18, CD54 (ICAM-1), CD58 (LFA-3), CD14, CD44, VLA-4, VLA-5, VLA-6, CD23, and CD25 (results not shown). These results indicate that the reduction in the antigen-presenting capacity of monocytes is not due to inhibition of intercellular adhesion molecules that either directly (26,27), or by mediating T cell APC contacts, play an important role in T cell activation and proliferation. The observation that the APC function of EBV-LCL was not affected by II:10 and v-IL-10 tested over a wide concentration range and after prolonged incubation times (up to 4 d), together with the fact that IL-10 and v-Ibl0 failed to downregulate class II MHC expression on these cells, suggested that the reduction in antigen-specific proliferative responses of CD4 + T cells and T cell clones could be associated with the strong reduction in surface class II MHC expression on the monocytes.…”

Crosslinking of the T cell-specific accessory molecules CD7 and CD28 modulates T cell adhesion.

“…shown that the phorbol ester PMA, mitogenic pairs of CD2 mAbs, or mAb crosslinking of the CD3/TCR results within minutes in increased adhesion via LFA-1 to ICAM-1 (3,5,6), via the VLA integrins VLA-4 and VLA-5 to FN, and via VLA-6 to LN (4,5). The data in Fig.…”

“…Regulation of the functional activity of these adhesion molecules is critical to both T cell migration and recognition, since T cells must transiently interact with cells and proteins found in the extracellular environment. One important element in the regulation of adhesion is the rapid increase in the adhesive function of integrin molecules that occurs after crosslinking of the CD3/TCR complex by mAb (3)(4)(5)(6) or foreign antigen (7). Integrins mediate T cell adhesion to other cells via interactions such as LFA-1 binding to its ligands ICAM-1 and ICAM-2, and VLA-4 binding to VCAM-1, and also to extraceUular matrix (ECM) 1 components via interactions such as VLA-4 and VLA-5 to fibronectin (FN) (1,2,8).…”

Principles of tumor immunosurveillance and implications for immunotherapy

“…58,60,63,64 Additional second signals include members of the TNFR family (CD40 -CD40L, CD27 -CD70, OX40-OX40L, 4 -1BB -4 -1BBL, and others ) 65 -68 as well as soluble molecules such as IL-2, IL -12, and IL -18 69 and molecules involved in cell adhesion and T-cell stimulation such as LFA -1 and ICAM -1. 70 The two -signal hypothesis originally explained contact-dependent cooperation of CD4 + T cells and B cells 58 but was then extended generally to induction of T cells. 59 Although activation of CD8 + T cells may be less dependent on costimulation than activation of CD4 + T cells, expression of costimulatory molecules or cytokines has been shown to variably enhance CTL activation and proliferation, 64,69 and offers rationales to explain the lack of antitumor immunity as well as new possibilities for enhancement of such CTL responses.…”