Stimulation Through Intercellular Adhesion Molecule-1 Provides a Second Signal for T Cell Activation

Chirathaworn, Chintana; Kohlmeier, Jacob E.; Tibbetts, Scott A.; Rumsey, Lisa M.; Chan, Marcia A.; Benedict, Stephen H.

doi:10.4049/jimmunol.168.11.5530

Cited by 102 publications

(84 citation statements)

References 53 publications

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“…In addition to mediating ICAM-1 adhesion, it can generate outside-in signals that costimulate T cells (25,41,42). The nature of the outside-in pathway has been unclear, but may involve PYK-2 (proline-rich tyrosine kinase 2) and FAK (24,25).…”

Section: Discussionmentioning

confidence: 99%

SLP-76-ADAP adaptor module regulates LFA-1 mediated costimulation and T cell motility

Wang

Wei

Bismuth

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Although adaptor ADAP (FYB) and its binding to SLP-76 has been implicated in TcR-induced ''inside-out'' signaling for LFA-1 activation in T cells, little is known regarding its role in LFA-1-mediated ''outsidein'' signaling. In this study, we demonstrate that ADAP and SLP-76-ADAP binding are coupled to LFA-1 costimulation of IL-2 production, F-actin clustering, cell polarization, and T cell motility. LFA-1 enhancement of anti-CD3-induced IL-2 production was completely dependent on SLP-76-ADAP binding. Further, anti-CD3 was found to require CD11a ligation by antibody or ICAM1 to cause T cell polarization. ADAP augmented this polarization induced by anti-CD3/CD11a, but not by anti-CD3 alone. ADAP expression with LFA-1 ligation alone was sufficient to polarize T cells directly and to increase T cell motility whereas the loss of ADAP in ADAP؊/؊ primary T cells reduced motility. A mutant lacking SLP-76-binding sites (M12) blocked LFA-1 costimulation of IL-2 production, polarization, and motility. LFA-1-ADAP polarization was also dependent on src kinases, Rho GTPases, phospholipase C, and phosphoinositol 3-kinase. Our findings provide evidence of an obligatory role for the SLP-76-ADAP module in LFA-1-mediated costimulation in T cells.outside-in signaling ͉ T cell activation I ntegrins are transmembrane receptors that mediate cell adhesion, motility, proliferation, and differentiation. T lymphocytes express at least 12 integrins with ␣L␤2, leukocyte function-associated antigen-1 (LFA-1) also termed CD11aCD18, binding to intracellular adhesion molecule (ICAM)-1, -2, and -3 (1-3). Whereas LFA-1 is in a low-affinity state on resting cells, ligation by the antigen-receptor complex (TCR/CD3) generates ''inside-out'' signals that increase the avidity of binding by clustering (2, 3). Mediators involved in this process include CD4/CD8-Lck, IL2-inducible T cell kinase (ITK), the guanine nucleotide exchange factor Vav-1, phosphatidylinositol 3-kinase (PI 3K), Rap1 and its binding partner RapL (regulator of cell adhesion and polarization enriched in lymphoid tissues) or Riam (Rap1-interacting adaptor molecule), and adaptors SLP-76 (76-kDa src homology 2 domaincontaining leukocyte phosphoprotein), ADAP (adhesion and degranulation-promoting adaptor protein) [HUGO Gene Nomenclature: FYB-120/130 (Fyn-binding protein-120/130)], and SKAP1 [src kinase-associated phosphoprotein 1, also SKAP-55 (55-kDa src kinase-associated phosphoprotein)] (3, 4). SLP-76 is an immune cell adaptor with key N-terminal tyrosine residues and a C-terminal SH2 domain that binds to ADAP (5, 6). ADAP is also an adaptor with a unique N-terminal region, a canonical and a noncanonical SH3 domain, a putative Ena/VASP homology 1 (EVH1)-binding domain, and nuclear localization motifs (7,8). ADAP deficient T cells show defective LFA-1 clustering and adhesion (9, 10). SLP-76 SH2 domain binds to the 2 YDDV sites on ADAP (Y 595/651 DDV) (11-13). Mutation of the sites disrupts LFA-1 clustering and adhesion, localization at the periphery of the immunological synapse and T c...

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Section: Discussionmentioning

confidence: 99%

SLP-76-ADAP adaptor module regulates LFA-1 mediated costimulation and T cell motility

Wang

Wei

Bismuth

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…The ligation of ICAM-1 therefore represents an important event with the potential for greatly amplifying inflammation (15,51). Furthermore, in a recent study, signaling through ICAM-1 was shown to provide a co-stimulatory signal with that of CD3 leading to T cell proliferation and the induction of Th1 but not Th2 cytokines (52). In the present study, the pathways induced by binding to ICAM-1 were examined in detail to better understand the intracellular mechanisms involved in this response.…”

Section: Discussionmentioning

confidence: 99%

Selective Regulation of ICAM-1 and RANTES Gene Expression after ICAM-1 Ligation on Human Renal Fibroblasts

Blaber¹,

Stylianou²,

Clayton³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Leukocyte infiltration of the cortico-interstitium is characteristic of many forms of progressive renal disease. The principal adhesion molecule expressed on resident interstitial cells and recognized by leukocytes is intercellular adhesion molecule-1 (ICAM-1). ICAM-1 is an inducible transmembrane receptor, which forms the counter-receptor for the leukocyte ␤ 2 integrins. ICAM-1-dependent binding induces the synthesis of the chemokine RANTES and of ICAM-1 itself. This study examines some of the signaling pathways involved in this induction. After ICAM-1 cross-linking on fibroblasts, the mRNA and protein for both RANTES and ICAM-1 were induced. This induction was calcium-dependent and inhibited by BAPTA-AM. The p38, ERK1, and ERK2 MAP kinases were activated in a [Ca 2ϩ ] i -dependent manner, with a maximum phosphorylation at approximately 3 min after crosslinking. Through the use of selective inhibitors of p38 MAP kinase (SB203580) or MEKK (PD98059), p38 but not ERK activation was shown to be essential for the induction of ICAM-1. Neither was involved in RANTES activation, however. These mechanisms differed from those initiated by TNF-␣, which were not [Ca 2ϩ ] i -dependent. Electrophoretic mobility shift analysis demonstrated a time-dependent induction of both AP-1 and NF-B binding activity in nuclear extracts, maximal at approximately 15 min after ICAM-1 cross-linking. Only AP-1 activation, however, was calciumdependent, suggesting the central involvement of this transcription factor in ICAM-1 and RANTES induction after the ligation of ICAM-1. This study suggests an independent mechanism of inflammatory amplification, which may be characteristic of a persistent leukocytic involvement in areas of chronic inflammation rather than in cytokine-induced acute inflammation. steadmanr@cf.ac.uk An influx of leukocytes, particularly macrophages and lymphocytes, into the glomerulus and subsequently into the cortical interstitium is characteristic of most forms of progressive renal disease [see reference 1 for review and references 2-11). The initial interaction of the infiltrating cells is with the endothelial lining of the vessels. After migration through the endothelium, however, the principal interaction of leukocytes is with cortical fibroblasts, which, under inflammatory conditions, have the phenotypic appearance of myofibroblasts (8,(12)(13)(14)(15)(16). This interaction is mediated through the increased expression of intercellular adhesion molecule-1 (ICAM-1) (17-22) on the surface of the myofibroblasts and is central to the progression of inflammatory renal disease (2-11).ICAM-1 is a heavily glycosylated, single-chain transmembrane receptor induced by inflammatory cytokines at sites of inflammation, where it forms the counter-receptor for the leukocyte ␤ 2 integrins (23-25). We have recently demonstrated, for the first time, that leukocyte adherence to primary cultures of human renal fibroblasts was a stimulus for ICAM-1 induction (26). This induction was initiated as a result of the ICAM-1/␤ 2 integrin ...

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“…These molecules include LFA-1 (35) and ICAM (36) and these receptors may also use the mechanism of enhancing nuclear residence of NFATc1 to accomplish their costimulatory signals. nuc T cells.…”

Section: Discussionmentioning

confidence: 99%

Enhanced NFATc1 Nuclear Occupancy Causes T Cell Activation Independent of CD28 Costimulation

Pan¹,

Winslow²,

Chen

et al. 2007

The Journal of Immunology

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TCR signals induce the nuclear localization of NFATc proteins, which are removed from the nucleus after rephosphorylation by glycogen synthase kinase 3 and other kinases. Rapid nuclear export might allow continuous monitoring of receptor occupancy, making the transcriptional response proportional to the duration of TCR/CD28 signaling. To investigate this possibility, we analyzed mice in which T cells express a NFATc1 variant (NFATc1 nuc ) with serine-to-alanine changes at the glycogen synthase kinase 3 phosphorylation sites. NFATc1 nuc T cells have constitutively nuclear NFATc1, enhanced T cell activation in vivo, and calcineurin-independent proliferation in vitro. NFATc1 nuc T cells are hypersensitive to TCR/CD3 stimulation, resulting in enhanced proliferation and cytokine production that is independent of CD28 costimulation. These results support the notion that CD28 inhibits nuclear export of NFATc transcription factors. In addition, NFATc1 nuc destabilizes a positive feedback loop in which NFATc1 activates its own transcription as well as its targets, such as CD40 ligand and Th1/Th2 cytokines. The Journal of Immunology, 2007, 178: 4315-4321. Maximal and sustained activation of T lymphocytes requires integration of the signaling pathways downstream of the TCR and of coreceptors such as CD28 (1). Stimulation of naive T lymphocytes through their TCR in the presence of costimulation results in activation and proliferation while TCR stimulation alone can result in anergy or cell death. TCR stimulation activates the Ca 2ϩ /calcineurin-regulated calcineurin phosphatase complex. Calcineurin dephosphorylates and activates the NFATc family of transcription factors, the activation of which is required in T cells for the induction of antigenic and tolerogenic genetic programs (2). Concurrent CD28 costimulation of CD4 ϩ helper T cells results in the induction of genes that regulate cell cycle entry and promote survival as well as the expression of cell surface and secreted molecules that coordinate the immune response (3). The signaling pathways regulated by CD28 are controversial, but substantial evidence indicates that glycogen synthase kinase 3 (GSK3) 3 is inhibited by CD28, perhaps through a pathway involving PI3K and AKT (4, 5). GSK3 is also an important regulator of WNT signaling and apoptosis and plays critical roles in many biological systems (6).Genome-wide gene expression profiling indicates that one important aspect of CD28 signaling is the inhibition of GSK3, resulting in reduced nuclear export of nuclear NFATc proteins (7). Normally, nuclear export occurs when Dyrk1a and/or protein kinase A in the nucleus phosphorylate the serine/proline repeats and serine-rich region in the N termini of NFATc proteins (8). This primes NFAT for sequential phosphorylation by GSK3 (9 -12). Calcineurin inhibition affects the same group of genes as CD28 inhibition and to nearly the same degree, suggesting that reducing nuclear export of NFAT is an important functional consequence of CD28 signaling. CD28 stimulation is opposed by...

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Stimulation Through Intercellular Adhesion Molecule-1 Provides a Second Signal for T Cell Activation

Cited by 102 publications

References 53 publications

SLP-76-ADAP adaptor module regulates LFA-1 mediated costimulation and T cell motility

SLP-76-ADAP adaptor module regulates LFA-1 mediated costimulation and T cell motility

Selective Regulation of ICAM-1 and RANTES Gene Expression after ICAM-1 Ligation on Human Renal Fibroblasts

Enhanced NFATc1 Nuclear Occupancy Causes T Cell Activation Independent of CD28 Costimulation

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