Molecules that inhibit T-cell functions: cytochemical localization and shuttling (original) (raw)
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Journal of immunology (Baltimore, Md. : 1950), 1999
Since the functional outcome of effector T lymphocytes depends on a balance between activatory and inhibitory receptors, we studied the ability of CTLA-4 (CD152) to inhibit the cytolytic function of CTL. In 22 TCR alpha/beta+ CD3+ 8+ CTL clones, activation induced by anti-CD3, anti-CD28, or anti-CD2 mAb was inhibited by anti-CD152 mAb in a redirected killing assay. In eight clones inhibition was >40%, in 10 it ranged between 20-40%, and in four it was <20%. This suggests the existence of a clonal heterogeneity as well as for the ability of CTLA-4 to inhibit CD3/TCR-, CD28-, or CD2-mediated CTL activation. To support further this contention, we used an experimental model based upon Ag-specific CTL. Eight Ag-specific T cell clones that lyse autologous EBV-infected B lymphocytes, but are unable to lyse allogeneic EBV-infected B cell lines, were used in a cytolytic assay in which anti-CD152 mAb or soluble recombinant receptor (i.e., CTLA-4 Ig) were included. In this system, at var...
Journal of Experimental Medicine, 1984
Evidence for the functional involvement of T cell differentiation antigens inT cell recognition and/or activation has been provided by various studies in which antibodies to certain of these antigens have been shown to inhibit antigen-specific cytotoxicity (1-16), proliferation , and release of lymphokines (I 6, 20, 21). This phenomenon has been most extensively documented by studies that have utilized antibodies directed against the T8 molecule (22) (Lyt-2 in mouse), the T4 molecule (22) (L3T4 in mouse [23]), and the T3 molecule (22). To date, the available data suggest that the T3, T4, and T8 molecules are involved in T cell recognition or activation and are not involved in the lytic process. Models have been proposed in which the T4 and T8 molecules bind to nonpolymorphic structures on class II and class I MHC antigens (10, 16, 24), respectively, and that the T3 molecule is intimately associated with the T cell antigen-specific receptor (24).
Activation of lymphocytes by BAT and anti CTLA-4: comparison of binding to T and B cells
Immunology Letters, 1999
In this study we compare the binding and immune stimulatory properties of BAT and anti CTLA-4 monoclonal antibodies (mAbs). Both antibodies were previously shown to manifest effective immune responses against tumor cells. We have described that BAT antibody, produced against Daudi, a B lymphoblastoid cell line, binds and activates T cells. In this paper we demonstrate that anti CTLA-4, produced against the T-cell activation determinant CTLA-4, binds also to B lymphoblastoid cell lines like Daudi and Raji. Both antibodies do not bind resting B cells. BAT binds resting T lymphocytes as well as activated T lymphocytes, whereas anti CTLA-4 binds only activated T cells. Competitive binding experiments indicate that the binding sites of BAT and anti CTLA-4 on activated T cells are distinct. We have studied the in vitro stimulatory effect of BAT and anti CTLA-4 on lymphocytes cultured with or without tumor cells. In contrast to BAT that increased the proliferation of lymphocytes that have been cultured with tumor cells, anti CTLA-4 did not synergize with tumor cells to enhance lymphocyte proliferation.
Accumulation of CTLA-4 expressing T lymphocytes in the germinal centres of human lymphoid tissues'pa
Immunology, 1997
CTLA-4, a coreceptor with sequence homology to CD28 is expressed on T cells after activation. Mice deficient for CTLA-4 die young from massive infiltration of many organs by activated T cells, which highlights the essential inhibitory role the coreceptor plays in the regulation of the immune response. To study the prevalence and distribution of CTLA-4 in situ immunohistological analyses were carried out on human tonsils and lymph nodes. Expression of CTLA-4 was restricted to aef, T cells, and CTLA-4+ B cells were not observed. In T-cell areas, 2-10% of T cells were positive for CTLA-4 with similar percentages in the CD4+ and CD8+ subpopulations. In the germinal centres (GC) the fraction of CTLA-4+ T cells was much higher (70-90%). This was due to frequent expression of CTLA-4 on the CD4+ helper subpopulation. GC CD8+ T cells were rare and mostly did not express the coreceptor. The CTLA-4+ T-cell fraction was also overrepresented among intraepithelial tonsillar T cells. Cycling (Ki-67+) and apoptotic (TUNEL+) T cells were never positive for CTLA-4, while a subset of CD25 + cells did express the coreceptor. Since CTLA-4 is essential for the physiological limitation of the immune response, GC T cells, which are mostly CTLA-4 positive, might be important in this process.
Cloned cytotoxic T lymphocytes as target cells. II. Polarity of lysis revisited
The Journal of Immunology
The original polarity of lysis experiments suggested that CTL are themselves sensitive to whatever mechanism it is that CTL use to lyse their targets. This concept has placed certain limitations on possible mechanisms of lysis by CTL. Recently, we found in studies with cloned CTL as targets that cloned CTL are in fact highly resistant to lysis by other CTL, as well as to their cytotoxic granule proteins. We show here that although cloned CTL are extremely resistant to lysis by primary and cloned CTL, they are readily inactivated functionally by all primary CTL and by at least one CTL clone. Moreover, cloned CTL are also functionally inactivated by cytotoxic granule proteins. The activation of CTL, which we call inhibitin, is Ca2+ insensitive and distinct from hemolytic activity, and is, thus, unlikely to be perforin. These experiments suggest a possible alternative interpretation of the original polarity of lysis experiments.