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M A Marcos

Publications and source records attributed to M A Marcos.

At least 91 records · Page 5Linked to original sources
PubMed1988

Alpha/beta heterodimeric T-cell receptor expression early in thymocyte differentiation.

The differentiation of T lymphocytes inside the thymus results in the acquisition of MHC-restricted specific functions mediated by clonally distributed alpha/beta heterodimeric T-cell receptors (TcR). Genes encoding the alpha and beta subunits of the clonotypic receptor (Ti) are rearranged during thymic ontogeny and expressed in association with the monomorphic CD3 complex. The regulation of the expression of functional TcR along T-cell development is thus crucial to establish the ontogenic events involved in the acquisition and selection of T-cell repertoires. Current views support that CD3-alpha/beta heterodimers are acquired late in ontogeny on developing thymocytes already expressing CD4 and/or CD8 surface molecules, whereas CD4- CD8- early precursors, representing the major population in the embryonic thymus, do not yet express the alpha/beta TcR. However, a novel CD3-associated gamma/delta heterodimer has been recently identified on the surface of this "double negative" subset both in thymocytes and in MHC-unrestricted peripheral T cells, suggesting that alpha/beta and gamma/delta heterodimeric receptors are independently expressed on the surface of distinct thymic subpopulations during T-cell development. In contrast to these results, we report here that a major proportion of CD3+1-4-8- adult human thymocytes, included within the early "double negative" subset, express alpha/beta heterodimeric receptors, as assessed by flow cytometric analysis using a frame-work monoclonal antibody (WT.31) against the alpha/beta TcR complex. These and previous data showing that CD3+1-4-8- "double negative" thymocytes constitute a functional intermediate ontogenic stage in the differentiation of CD3+1-4+8-/CD3+1-4-8+ mature T cells from CD3-1-4-8- early prothymocytes further support the relevance of the CD3+1-4-8- transitional subset as immediate intrathymic precursors of alpha/beta TcR-bearing mature T cells. Therefore, developmental regulation of alpha/beta TcR expression was analyzed at the DNA, RNA, and protein levels in those different thymic subpopulations, defined by both functional and phenotypic criteria. Our results demonstrate that multiple Ti beta gene rearrangements and beta RNA messages are already evident at the early prothymocyte stage. Moreover, expression of relative levels of both Ti alpha and Ti beta functional RNA transcripts, similar to those observed in mature thymic cells, were also present in CD3+1-4-8- thymocytes. According with these data, immunoprecipitation analysis using a specific anti-Ti alpha antisera revealed that both alpha and beta molecules are expressed on CD3+ "double negative" and mature thymocytes, but not in prothymocytes

Antigens, Differentiation, T-Lymphocyte↗
PubMed1987

Development of Ly-1+ B cells in immunodeficient CBA/N mice.

Spleen cells from CBA/N mice developing a systemic autoimmune disease after daily injection of CsA during an autologous bone marrow reconstitution were transferred into unmanipulated syngeneic recipients. Adoptive transfer allowed the development of Ly-1+ B cells, which shared Mac-1 differentiation antigen expression with the myelomonocytic lineage. Interestingly, expansion of formerly absent Ly-1+ B cells was paralleled by a severe reduction in common, Ly-1-, B cell development in the recipient. We conclude that precursors for Ly-1+ B lineage do exist in CBA/N mice.

Animals↗
PubMed1987

Interleukin 2 pathway is autonomously activated in human T11+3-4-6-8- thymocytes.

Mitogenic membrane ligands have been shown to activate interleukin 2 (IL2) production only in mature T cells, IL2 constitutive secretion having not yet been demonstrated. Here we have isolated a population of T11+3-4-6-8- human thymocytes and CD7+/T11-3-4-6-8- prothymocytes which produce and consume IL2 upon phytohemagglutinin triggering. Interestingly, their proliferation in the absence of any exogenous stimulating agent was related to an autonomous use of the IL2 system (IL2 secretion and binding to its specific receptor, whose constitutive, functional expression in human early thymocytes was recently shown). The internal activation of this system before T cell receptor acquisition stresses the relevance of the understanding of the alternative activation pathway(s) in T cell development. These findings, together with the demonstration of IL2-promoted differentiation of human early thymocytes into mature T cells, suggest that IL2 may also be a growth and differentiation factor acting specifically early in T cell development.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1987

A functional idiotypic network of T helper cells and antibodies, limited to the compartment of "naturally" activated lymphocytes in normal mice.

As shown previously, idiotype (Id) sharing between anti-2,4,6-trinitrophenyl T helper (Th) cells and antibodies in BALB/c mice results from immunoglobulin (Ig)-dependent selection of the T cell repertoire. In contrast, a clonotype defined by the same F6(51) anti-Id antibody is expressed by C57BL/6 anti-(4-hydroxy-3-nitrophenyl)acetyl Th cells independently of Ig influences. We have now used these systems to test the hypothesis that Ig-dependent Th cell repertoire selection occurs in the compartment of "naturally" activated lymphocytes. "Naturally" activated or resting splenic L3T4+ cells were separated from normal BALB/c and C57BL/6 mice and tested, either directly or after in vitro priming, in hapten-specific helper assays for expression of the clonotope defined by the F6(51) anti-Id antibody. The results show the selective expression of the antibody-dependent T cell Id in the "naturally" activated helper cell compartment. In contrast, when the T cell Id is expressed in the absence of Ig-dependent selection, it is only detected in the resting helper cell repertoire. Furthermore, BALB/c "natural" IgM antibodies with anti-Id specificities similar to F6(51) show functionally relevant interactions with syngeneic "naturally" activated Th cells. These are also characterized by high paratopic/Id degeneracy, as compared to helper cells obtained by conventional immunization. These results demonstrate repertoire differences between the set of (resting) lymphocytes participating in immune responses, vs. those "internally" activated in normal individuals. They also suggest the importance of Id network interactions in the compartment of "naturally" activated T and B cells.

Animals↗
PubMed1987

Turning (Ir gene) low responders into high responders by antibody manipulation of the developing immune system.

The ability of helper T cells directed against trinitrophenyl-modified syngeneic spleen cells to recognize low-hapten densities on target cells is under major histocompatibility complex-linked Ir gene control. Thus, BALB/c (H-2d) mice are low responders while H-2 congenic BALB.C3H (H-2k) mice are high responders. Immunization of adult BALB/c mice with the monoclonal antibody F6(51), directed to shared idiotopes by anti-trinitrophenyl antibodies and clonal receptors on anti-trinitrophenyl-self helper T cells, leads to the production of high titers of circulating idiotype, has no influence on helper T cell idiotypic profiles, but shifts to a high-responder phenotype the ability of helper T cells to recognize low-hapten densities. These effects on Ir gene phenotype are even more striking in untreated progenies from F6(51)-immunized BALB/c females, which are better responders than genetically high-responder BALB.C3H mice, although completely different in the expression of the F6(51)-defined clonotype. The general significance of these findings on Ir gene-directed T-cell repertoire selection is discussed, for they constitute formal evidence against antigen-presentation as a mechanism of Ir gene effects and strong support for the importance of maternal influences on the development of T-cell repertoires.

Animals↗
PubMed1987

Sporadic idiotypic cross-reactivities between antibodies and T helper cells: one example of aleatory expression of T cell idiotypes.

Idiotypic cross-reactivities between T and B cell receptors have been taken in the past to suggest VH-gene expression by both types of lymphocytes. More recently, after the molecular characterization of TcR, those observations were reinterpreted to indicate idiotypic network regulation, operating to select cross-reactive idiotypes in both B and T cell compartments. In support of these views, it has been shown that T cell expression of idiotypes is controlled by IgH-linked genes and markedly altered in B cell-deprived mice, and that T cells "learn" idiotype expression from the B cell compartment in the first few weeks of life. In most of these studies, aleatory idiotype cross-reactivities have not been sufficiently considered. Given the large diversity of antibodies and TcR, and the degeneracy of antibody-ligand interactions, it could be expected that a (monoclonal) anti-idiotypic reagent prepared against an antibody idiotope will always "cross-react" with some TcR variable regions. If these will be "major" T cell clonotypes, situations of idiotype sharing by B and T cells can be found which indicate neither VH-gene expression by T cells nor idiotypic network regulation. We report here one example of such aleatory expression of antibody idiotypes by T lymphocytes. A monoclonal anti-idiotypic antibody directed to anti-TNP antibodies of BALB/c mice specifically inhibits the growth and effector activity of C57BL/6 anti-NP-self helper T cells, while failing to interact with either BALB/c anti-NP-self or C57BL/6 anti-TNP-self helper cells. The clonotypic nature of these interactions could also be demonstrated by the specific induction of IL-2 production in the appropriate helper T cells by the anti-idiotypic antibody.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Differentiation of human mature thymocytes: existence of a T3+4-8- intermediate stage.

A T3 complex-bearing subpopulation was characterized within an in vivo cycling T4-8- early thymocyte compartment which contains cells constitutively expressing interleukin 2 and transferrin receptors. We show differentiation in vitro of both mature subsets of thymocytes (T3+4+8- and T3+4-8+) from the above T4-8- compartment, their appearance being preceded by cells in a T3+4-8- intermediate stage. Furthermore, those mature thymocytes generated in vitro contain functionally competent cells which use T3, T4 and T8 structures for their cytolytic activity. The finding of T3+4-8- thymocytes in vivo, together with the observation that T3 antigen expression precedes that of T4 or T8 molecules in vitro, shows that T3 (and presumably Ti) is present early in ontogeny, and suggests that T3+4-8- cells constitute an "intermediate" stage relevant to the connection between early precursors and mature thymocytes during T lymphocyte ontogeny.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1986

A role for T3+4-6-8- transitional thymocytes in the differentiation of mature and functional T cells from human prothymocytes.

In vivo, immunocompetent T lymphocytes are only detected late in ontogeny, among mature thymocytes expressing either T4 (L3T4 in mouse) or T8 (Lyt-2) surface glycoproteins. We have previously shown, however, that there are functional precursors among T3+4-6-8- human thymocytes in vivo. Here we report on the in vitro differentiation of prothymocytes into T3+4-6-8- and mature T cells. T11+3-4-6-8- prothymocytes (0.5% of total thymocytes, greater than 98% pure) were obtained after treatment of thymocytes with OKT3 (T3), OKT4A (T4), Na1/34 (T6), and B9.4 (T8) monoclonal antibodies plus complement. During culture, the prothymocyte precursors acquire first T3 and then either T4 or T8, but not T6. The largest subpopulation in the thymus, T4+6+8+ cells, are not detected among the in vitro T-cell precursors. During culture, the precursors acquire cytolytic activity as soon as they express either the T3+4-6-8- or the mature (T3+4+8- or T3+4-8+) phenotypes. We suggest that T3+4-6-8- cells are a productive, transitional stage in T-lymphocyte development.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1986

Functional and biochemical evidence for the recognition of T cell receptors by monoclonal antibodies to an immunoglobulin idiotype.

Sharing of "idiotypes" by T and B cells with similar nominal specificities has been extensively reported in functional assays. The recent molecular characterization of T cell receptors has led to the suggestion that such idiotypic mimicries could result from "network" selection of available T cell repertoires. Alternatively, the validity of the conclusions taken from those functional assays could be questioned. We have now used an experimental system where recurrent expression of antibody idiotypes by T helper cells requires "learning" from the B cell/antibody compartment, and show here that the idiotypic determinants in question are indeed associated with T cell receptor molecules. A monoclonal antibody (F6(51)) directed to an idiotope of the TNP-binding BALB/c myeloma protein MOPC460 specifically inhibits antigen-dependent proliferation and helper activity of BALB/c anti-TNP-BALB/c helper T cells. The anti-idiotypic antibodies also induce IL-2 production by these helper cells and precipitate a surface molecule with characteristics of T cell receptor. We conclude that, in this particular system, T cell receptors and antibodies of similar nominal specificities share idiotypic determinants.

Animals↗