Role Of Lymphocyte Function-associated Antigen-1 Research Articles

Role of LFA-1 in the activation and trafficking of T cells: implications in the induction of chronic colitis.

We have previously demonstrated that adoptive transfer of naïve CD4(+) T cells devoid of lymphocyte function-associated antigen-1-deficient (LFA-1; CD11a/CD18) into recombination activating gene-1 (RAG-1) deficient (RAG(-/-) ) mice fails to induce chronic colitis whereas transfer of wild type (WT) T-cells induces unrelenting and chronic disease. The objectives of this study were to assess the role of lymphocyte function-associated antigen-1 (LFA-1) in enteric antigen (EAg)-induced activation of T cells in vitro and in vivo and to define the importance of this integrin in promoting trafficking of T cells to the mesenteric lymph nodes (MLNs) and colon. We found that EAg-pulsed dendritic cells (DCs) induced proliferation of LFA-1-deficient (CD11a(-/-) ) CD4(+) T cells that was very similar to that induced using WT T cells, suggesting that LFA-1 is not required for activation/proliferation of T cells in vitro. Coculture of WT or CD11a(-/-) T cells with EAg-pulsed DCs induced the generation of similar amounts of interferon-gamma, interleukin (IL)-4, and IL-10, whereas IL-17A production was reduced ≈ 2-fold in cocultures with CD11a(-/-) T cells. Short-term (20-22 hours) trafficking studies demonstrated that while both WT and CD11a(-/-) T cells migrated equally well into the spleen, liver, lungs, small intestine, cecum, and colon, trafficking of CD11a(-/-) T cells to the MLNs was reduced by 50% when compared to WT T cells. When the observation period was extended to 3-7 days posttransfer, we observed ≈ 2-3-fold more WT T cells within the MLNs and colon than CD11a(-/-) T cells, whereas T-cell proliferation (as measured by CFSE dilution) was comparable in both populations. Taken together, our data suggest that LFA-1 is not required for EAg-induced activation of CD4(+) T cells in vitro or in vivo but is required for trafficking of T cells to the MLNs and homing of colitogenic effector cells to the colon where they initiate chronic gut inflammation.

The Role of LFA-1 in T cell Trafficking and Functions in Demyelinating Disease (99.5)

Abstract Multiple sclerosis (MS) is characterized by autoimmune damage to central nervous system (CNS) myelin, resulting in impaired nerve function. Integrins such as lymphocyte function-associated antigen-1 (LFA-1) are thought to be important in leukocyte trafficking to the CNS and disease development. Studies using monoclonal antibodies to LFA-1 in experimental autoimmune encephalomyelitis (EAE), the animal model for MS, have provided conflicting results regarding the role of LFA-1 in EAE. To overcome the limitations of the antibody-based approach, we used LFA-1-deficient mice and a transgenic mouse (T-lux) with a hCD2 promoter that drives expression of the luciferase gene specifically in T cells thereby providing a novel method of a real-time depiction of T cell trafficking patterns. We found that both LFA-1-deficient and LFA-1 hemizygous mice do not develop clinically significant EAE and have markedly reduced leukocyte infiltration into the CNS. Encephalogenic LFA-1-deficient T-lux cells adoptively transferred into wild type recipients do not localize to the CNS, whereas MOG-specific wildtype T-lux cells transferred to wildtype or LFA-1-deficient recipients, readily migrate to the CNS and draining lymph nodes and proliferate. These data demonstrate that LFA-1 on T cells is necessary for myelin-specific T cells to enter into the CNS and initiate disease. Supported by NIH grant NS46032.

Distinct role of lymphocyte function-associated antigen-1 in mediating effective cytolytic activity by cytotoxic T lymphocytes

Lymphocyte function-associated antigen-1 (LFA-1) interaction with intercellular adhesion molecules (ICAMs) facilitates T cell antigen receptor (TCR)-mediated killing. To dissect TCR and LFA-1 contributions, we evaluated cytolytic activity and granule release by cytotoxic T lymphocytes (CTL) as well as intracellular granule redistribution and morphology of CTL stimulated with natural TCR ligand in the presence or absence of LFA-1 engagement. Although other adhesion mechanisms, e.g., CD2-CD58 interaction, could substitute for LFA-1 to trigger CTL degranulation, productive LFA-1 ligation was indispensable for effective target cell lysis by the released granules. LFA-1-mediated adhesion to glass-supported bilayers containing intercellular adhesion molecule-1 was characterized by a much larger junction area, marked by LFA-1 segregation, and a more compact cell shape compared with those observed for CD2-mediated adhesion to bilayers containing CD58. A larger contact induced by intercellular adhesion molecule 1 determined a unique positioning of granules near the interface. These data provide evidence that LFA-1 delivers a distinct signal essential for directing released cytolytic granules to the surface of antigen-bearing target cells to mediate the effective destruction of these cells by CTL.

Treatment with anti‐LFA‐1α monoclonal antibody selectively interferes with the maturation of CD4−8+ thymocytes

Maturation of T lymphocytes in the thymus is driven by signals provided by soluble factors and by the direct interaction between thymocytes and stromal cells. Although the interaction between T-cell receptor (TCR) and major histocompalibility complex (MHC) molecules on stromal cells is crucial for T-cell development, other accessory molecules seem to play a role in this process. In order to better understand the role of lymphocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) molecules in thymocyte maturation, mice were treated from birth with saturating doses of non-cytolytic-specific monoclonal antibodies. The effect of this treatment on thymocyte subpopulations and the expression of CD3 and TCR-alpha beta by these cells was investigated by flow cytometry. Our data demonstrated that the effective saturation of LFA-1 alpha chain in the thymus, but not ICAM-I or LFA-I beta chain, selectively interfered with the maturation of CD8+ T cells, as manifested by a marked reduction in the frequency of CD4-8+ thymocytes expressing high levels of CD3 and TCR-alpha beta. This selective reduction was also observed in peripheral blood mononuclear cells and spleen cells. The analysis of the frequencies of various V beta TCR showed that CD4-8+ thymocytes were globally affected by the treatment. These results underline the importance of the interaction between LFA-1 and its ligands in the maturation of CD8+ T cells and document the existence of different molecular requirements for the differentiation of CD4+ and CD8+ T cells.

Activation of Cord T Lymphocytes: III. Role of LFA-1/ICAM-1 and CD2/LFA-3 Adhesion Molecules in CD3-Induced Proliferative Response

As cord T cells, a Model of antigen (Ag)-unprimed cell, display a functional defect when stimulated through the CD3 molecule, the role of lymphocyte function-associated antigen 1(LFA-1)/intercellular adhesion molecule 1 (ICAM-1) and CD2/lymphocyte function-associated antigen 3 (LFA-3) receptor-ligand pairs in cord CD3-triggered T-cell activation was analyzed using specific monoclonal antibodies (mAb) against each adhesion molecule. The addition of anti-CD11a, anti-CD18, or anti-CD2 to both adult and cord peripheral blood mononuclear cells (PBMC) cultures led to a decrease in CD3-induced proliferation. In contrast, CD3-stimulated cord, but not adult, PBMC proliferation was markedly enhanced when anti-CD54 or anti-CD58 were added. Despite the fact that ICAM-1 and LFA-3 molecules were virtually absent on cord resting T cells, mAb against these two molecules boosted both mitogenesis of and interleukin (IL)-2 production by purified cord T cells stimulated with plastic immobilized anti-CD3. Cord T-cell supernatant levels of interferon-γ (IFN-γ) were undetectable with CD3 stimulation, slightly raised with CD58/CD3 costimulation, but normal when T cells were preincubated with IL-2 for 24 hr before being costimulated with anti-CD3/CD58. Evidence that IL-2 and IFN-γ play a pivotal role in fully activating cord T cells came from the demonstration that IL-2 and IFN-γ are able to bypass the CD3-proliferative defect through differential up-regulation of the adhesion molecules. It would, therefore, seem that ICAM-1 and LFA-3 molecules are crucially implicated in the CD3-activation pathway of Ag-unprimed T cells.

Role of lymphocyte function-associated antigen-1 (LFA-1) in the migration of T cells to lymphocyte chemotactic factor (LCF) and IL-2

Role of lymphocyte function-associated antigen-1 (LFA-1) in the migration of T cells to lymphocyte chemotactic factor (LCF) and IL-2

The role of LFA-1 in class II restricted, antigen-specific T-cell responses.

We have studied the role of the murine lymphocyte function associated antigen-1 (LFA-1) in the major histocompatibility complex (MHC)-restricted responses of a panel of T-cell hybridomas to protein antigens. Monoclonal antibodies to LFA-1 showed a differential blocking effect in these responses that correlated with the overall "sensitivity" of a given hybrid to antigen and MHC as defined by other criteria already reported. This result differs completely from similar experiments in the CTL system where all clones regardless of their overall "avidity" for target cells are very sensitive to the blocking effects of anti-LFA-1. Further, we show that no blocking effects are observed in the response of our hybridomas when Class I or Class II transfected fibroblasts or cultured 3T3 fibroblasts are used as synthetic antigen presenting cells and the result is unaltered by preincubation of such cells with interferon-gamma (IFN-gamma).