Developmental control of integrin expression regulates Th2 effector homing.

Integrin CD18, a component of the LFA-1 complex that also includes CD11a, is essential for Th2, but not Th1, cell homing, but the explanation for this phenomenon remains obscure. In this study, we investigate the mechanism by which Th2 effector responses require the LFA-1 complex. CD11a-deficient T cells showed normal in vitro differentiation and function. However, Th2 cell-dependent allergic lung disease was markedly reduced in CD11a null mice and wild-type mice given LFA-1 inhibitors, whereas control of infection with Leishmania major, a Th1-dependent response, was enhanced. In both disease models, recruitment of IL-4-, but not IFN-gamma-secreting cells to relevant organs was impaired, as was adhesion of Th2 cells in vitro. These diverse findings were explained by the markedly reduced expression of CD29, an alternate homing integrin, on Th2, but not Th1, cells, which precludes Th2 homing in the absence of CD11a. Thus, murine Th1 and Th2 cells use distinct integrins for homing, suggesting novel opportunities for integrin-based therapeutic intervention in diverse human ailments influenced by Th2 cells.

Deficiency of CD11b or CD11d results in reduced staphylococcal enterotoxin-induced T cell response and T cell phenotypic changes.

The beta(2) integrin CD11a is involved in T cell-APC interactions, but the roles of CD11b, CD11c, and CD11d in such interactions have not been examined. To evaluate the roles of each CD11/CD18 integrin in T cell-APC interactions, we tested the ability of splenocytes of CD11-knockout (KO) mice to respond to staphylococcal enterotoxins (SEs), a commonly used superantigen. The defect in T cell proliferation with SEA was more severe in splenocytes from mice deficient in CD18, CD11b, or CD11d than in CD11a-deficient splenocytes, with a normal response in CD11c-deficient splenocytes. Mixing experiments showed that the defect of both CD11b-KO and CD11d-KO splenocytes was, unexpectedly, in T cells rather than in APC. Cytometric analysis failed to detect CD11b or CD11d on resting or activated T cells or on thymocytes of wild-type adult mice, nor did Abs directed to these integrins block responses in culture, suggesting that T cells educated in CD11b-KO or CD11d-KO mice were phenotypically altered. Consistent with this hypothesis, T cells from CD11b-KO and CD11d-KO splenocytes exhibited reduced intensity of CD3 and CD28 expression and decreased ratios of CD4/CD8 cells, and CD4(+) T cells were reduced among CD11b-KO and CD11d-KO thymocytes. CD11b and CD11d were coexpressed on a subset of early wild-type fetal thymocytes. We postulate that transient thymocyte expression of both CD11b and CD11d is nonredundantly required for normal thymocyte and T cell development, leading to phenotypic changes in T cells that result in the reduced response to SE stimulation.

Host resistance of CD18 knockout mice against systemic infection with Listeria monocytogenes.

Mice with targeted mutations of CD18, the common beta2 subunit of CD11/CD18 integrins, have leukocytosis, impaired transendothelial neutrophil emigration, and reduced host defense to Streptococcus pneumoniae, a gram-positive extracellular bacterium. Previous studies using blocking monoclonal antibodies suggested roles for CD18 and CD11b in hepatic neutrophil recruitment and host innate response to Listeria monocytogenes, a gram-positive intracellular bacterium. We induced systemic listeriosis in CD18 knockout (CD18-ko) and wild-type (WT) mice by tail vein injection with Listeria. By 14 days postinjection (dpi), 8 of 10 WT mice died, compared with 2 of 10 CD18-ko mice (P < 0.01). Quantitative organ culture showed that numbers of Listeria organisms in livers and spleens were similar in both groups at 20 min postinfection. By 3, 5, and 7 dpi, however, numbers of Listeria organisms were significantly lower in livers and spleens of CD18-ko mice than in WT mice. Histopathology showed that following Listeria infection, CD18-ko mice had milder inflammatory and necrotizing lesions in both spleens and livers than did WT mice. Cytokine assays indicated that baseline interleukin-1beta and granulocyte colony-stimulating factor (G-CSF) levels were higher in CD18-ko mice than in WT mice and that CD18-ko splenocytes produced higher levels of interleukin-1beta and G-CSF than WT splenocytes under the same amount of Listeria stimulation. These findings show that CD18 is not an absolute requirement for antilisterial innate immunity or hepatic neutrophil recruitment. We propose that the absence of CD18 in the mice results in the priming of innate immunity, as evidenced by elevated cytokine expression, and neutrophilic leukocytosis, which augments antilisterial defense.

Differential requirement for CD18 in T-helper effector homing.

To understand the integrin requirements of T-helper (T(H)) effector subsets, we investigated the contribution of CD18 (beta(2) integrin) to T(H)1 and T(H)2 function in vitro and in relevant disease models. CD18-deficient (Itgb2(-/-)) T cells showed largely normal in vitro function. Compared with wild-type mice, Itgb2(-/-) mice were better able to resolve Leishmania major infection and generated a superior T(H)1 immune response, as assessed from draining lymph nodes. In contrast, T(H)2-dependent allergic lung disease was markedly impaired in mutant mice. In both models, development of T(H)1 and T(H)2 cells in spleens was normal, but accumulation of T(H)2 (not T(H)1) cells at inflammatory sites was reduced. Thus, CD18 is selectively required for T(H)2, but not T(H)1, homing and has a minimal influence on T-effector development. These findings suggest a new integrin-based therapeutic approach in which the outcomes of diverse diseases may be favorably influenced by altering the homing of T(H)2 cells.

16. Immunologic lung disease.

This review summarizes the recent advances regarding pathogenesis, diagnosis, and treatment of immunological diseases of the lung. Rather than attempt a comprehensive analysis, we have focused on selected diseases that are of particular relevance to the practicing physician, and the material has been organized according to the dominant immunologic mechanisms underlying the disease. Because of the redundancy that characterizes the mammalian immune repertoire, this system of classification inevitably produces overlap but facilitates acquisition of what is otherwise a disparate collection of facts. The principal lung immunologic mechanisms are most broadly classified as innate or adaptive immune processes. Innate immunity includes neutrophils and complement that are important in diseases, such as pneumonia and the acute respiratory distress syndrome. Adaptive immunity involves T and B cells capable of recognizing discrete antigens. T(H)1- and T(H)2-dependent adaptive immune responses underlie some of the most common and important of lung diseases, including tuberculosis and asthma, respectively. Other important immunopathologic processes include granulomatous inflammation that characterizes sarcoidosis and Churg-Strauss vasculitis, and autoimmunity, which is characteristic of antiglomerular basement membrane disease and others.