Carlos Márquez

Human T‐Cell Precursors: Involvement of the IL‐2 Pathway in the Generation of Mature T Cells

Despite the genetic and structural homoiogy between antigen recognition receptors expressed by both T and B cellular components of the immune system (Kronenberg et al. 1986), T-cell recognition appears to be restricted by the products of the major histocompatibility complex (MHC) (Kindred & ShrefTler 1972, Katz et al. 1973, Zinkernagei & Doherty 1974). Acquisition of MHCrestricted T-ccll function is related to the many, and yet poorly understood, selective and muturational events which take place in the thymus (Fink & Bevan 1978, von Boehmer et ai. 1978, Sprent 1978, Zinkernagel 1978, Moller 1988). Committed hematopoietic T-cell precursors colonize the thymus during ontogeny, undergo a complex developmental process leading to the expression of clonallydistributed T-cell receptors (TCR) and migrate to the periphery as immunocompetent mature T cells (Moller 1984a). Attempts in the past few years to delineate such developmental events led to the characterization of distinct thymus subpopulations by means of the ditTerential expression of various cell surface molecules. Based on phenotypic and functional criteria, further reinforced by molecular genetic approaches, increasing agreement was reached between different laboratories when trying to correlate these subsets with discrete stages of development (reviewed by Moller 1984a). Careful analyses of cell dynamics within the thymus have allowed a better appreciation of the contribution of each thymic subpopulation to the general developmental process (Scollay & Shortman 1984, Scollay et al. 1984). Although the normal rate of stem-cell seeding into the thymus is extremely low, there is an extensive and rapid

The Participation of B Cells and Antibodies in the Selection and Maintenance of T Cell Repertoires

The imtnune system (IS) of vertebrates is endowed with obvious cognitive properties: it learns, remembers, and makes discriminatory inferences about molecular profiles. Typically, properties of this nature cannot be ascribed to individual components in the system (in our case, to the presence or activity of given clones), but they emerge as global behaviors from its general organization. Immune self/ nonself discrimination is, thus, a characteristically dispersed property of the IS (Varela et al. 1987). It follows that, to understand self/nonself discrimination, we have to be concerned at least as much v̂ fith such global behaviors and distributed properties as with individual clonal specificities. Distributed properties require connectivity between the elements of the system, and of these with other self components. Therefore, we believe, the understanding of self/nonself discrimination must start from the consideration of self-directed reactivities, in clear contrast with the classical notion that immune self/nonself discrimination is based upon the elimination of self-reactive clones (Vaz et al. 1984. Coutinho et al. 1984). Clearly, and this is also the case for conventional points of view, the behavior of an IS at any point in life can only be understood in the context of its own history in the ontogenic development of the individual. Snapshots of adult immune systems based on the study of lymphocyte repertoires, while necessary to realize the structure of the systems components and to construct the anatomy of interactions, will always tell us little about history and overall organization. We must therefore make explicit here the limitations of an approach (clonal

Signal Transduction Pathways Involved in B‐Cell Induction

B lymphocytes fulfil two cardinal functions in the immune system. On one hand, B cells are directly involved in immune responses as immune effector cells, integrating the humoral immune system. On the other hand, they serve as highly selective antigen-presenting cells endowed with the capacity to selectively capture antigen and to present it to T lymphocytes, thus determining whether a T-cell response will be aborted or stimulated. The distinctive surface structure of the B lymphocyte is the B-cell receptor (BCR) made up by membrane immunoglobulin (Ig) in association with several invariant chains that exert a signal-transducing function. Depending on the differentiation and activation stage of the B cell, the nature, concentration and affinity/avidity of the crosslinking agent, as well as on additional signals simultaneously delivered to the cell via receptors for cytokines, bacterial products, matrix proteins and cell surface determinants of neighboring cells, crosslinking of surface Ig (sig) may result in rather different biological responses, namely activation, antigen presentation, proliferation, induction of Ig secretion, cellular differentiation, growth arrest, inhibition of Ig production, or induction of programmed cell death (PCD). Recent studies are tentatively shedding light on the black box that contains the complicated machinery linking slgmediated signals to different biological responses in B cells. This review will discuss the essential ingredient of the BCR and the signal-transducing cascade involved in B-cell stimulation.

Mutual cell interactions and the selection of immune repertoires: implication in autoimmunity

Abstract The predominant neonatal lymphocyte subset - (CD5/Ly 1) + B cells and CD3 + CD4 − CD8 − T cells - can react extensively with self antigens. In this article, Miguel Marcos and colleagues point out similarities between these subsets, and postulate a role for their mutual interactions, and interactions with the conventional cell types found in adults, in the selection of mature lymphocyte repertoires and in the control of autoimmune phenomena. A disturbance in the equilibrium between these various cells may be an important factor in the development of autoimmunity.

Lack of correlation betwen translocation and biological effects mediated by protein kinase C: an appraisal

Protein kinase C is involved in the mechanism of action of hormones, growth factors, mitogens and tumour promoters. The correlation between the extent of the biological effects mediated by protein kinase C and its fractional activation shows cell type specific patterns of behaviour. The discrepancy between enzyme activity and biological effects elicited by protein kinase C is particularly relevant to lymphoblastic cells. In B cells, the full expression of some biological responses mediated by protein kinase C may be achieved by activation of less than 5% of the enzyme activity.

Modification of Emerging Repertoires by Immunosuppression in Immunodeficient Mice Results in Autoimmunity

One of the fundamental paradigms in immunology has been that the Immune System does not react against the soma and every theory which has attempted to explain the immune response has had to account for the lack of autoreactivity. In those cases where responses to self have been clearly demonstrated, these have been termed autoimmune disease. Yet with 80 years of this paradigm behind us, we have slipped into a new era in which the paradigm has been reversed and reactions against self are used to explain both the initiation and regulation of the immune response. Thus, autoreactivity to major histocompatibility complex (MHC) products is necessary to generate an immune response (the ZinkernagelDoherty-Shearer phenomenon; Moller 1978) and anti-idiotypic interactions may play a crucial role in the regulation of the immune system (Jerne 1974, Moller 1984, 1986). Furthermore, we have recently extended self-recognition within the polymorphic structures (Immunoglobulins (Igs), T-cell receptors (TCR) and MHC antigens) to all other components of the internal environment that have been incorporated into self to an immunosomatic perspective (Vaz et al. 1984). In fact, a large body of evidence has been accumulated in the past indicating the existence of immune reactivity directed toward self-components, as a result of the natural internal activity of the Immune System {Coutinho et al. 1985). Such

Selective Expansion of a CD3+CD4‐CD8‐ Subpopulation in Clinical Groups Associated with Human Immunodeficiency Virus Infection

T lymphocytes (CD3+) without expression of CD4/CD8 surface antigens have recently been described in the thymus and peripheral tymphoid organs. We have conducted a retrospective analysis of the literature, seeking quantitative variations in this T‐cell subset in normal heterosexual controls, and in risk, pre‐AIDS, and AIDS groups, by means of the subtraction [CD3‐(CD4+CD8)] and the ratio 100×[CD3‐(CD4+CD8)]/CD3. Dramatic T lymphocytopaenia in AIDS patients and the progressive decay of CD4+ lymphocytes and increase of CD8+ lymphocytes throughout the clinical spectrum of HIV infection have been confirmed. Furthermore, we hereby demonstrate the selective expansion of CD3+CD4−CD8− lymphocytes, directly related to the clinical state in different clinical groups of infected people when compared with controls (P<0.05). The inverse relationship between the CD3+CD4−CD8− cell subset and other mature T‐cell subsets, mainly CD4+ (r=−0.49; P<0.01). suggests the existence of mutual regulatory interactions. These in vivo results, which are in agreement with those obtained in long‐term infected cultures, cannot be explained by direct cytopathic effects of the virus on the very few infected cells. Thus, the implication of the expansion of these functional precursors on the prognosis for infected people, and the paradoxes of the immunodeficiency, such as lymphoproliferation and autoimmune features, are discussed.

A Hypothesis for the Selection of Available Repertoires: T‐Cell Network Early in the Intrathymic Differentiation

T‐cell recognition requires direct cell‐cell interactions mediated by major histocompatibility complex (MHC)‐restricted α‐β heterodimeric receptors (Ti) in association with a constant protein complex termed T3 (TcR, Ti‐T3). Interleukin 2 (IL‐2) promotes growth and maturation of T cells upon binding to high affinity receptors (IL2‐R). They are expressed after the recognition of antigen on accessory cells through the TcR [44]. Furthermore, current hypotheses propose that T‐cell interactions are also mediated by a group of T‐cell antigens, particularly T4/L3T4 and T8/Lyt 2 [35], and perhaps Tγ [15]. All their encoding genes are rearranged and/or expressed sequentially during thymocyte differentiation [5, 8, 40, 41, 46, 51, 52]. Thus, developmental analyses of T‐cell function are essential to gain insight into the mechanisms for selection of available repertoires, one of the central problems in immunology.

Translocation of alkaline phosphatase during the activation of B cells.

The association of alkaline phosphatase (ALPase) with the cytoskeleton in lymphoid cells was investigated. Extracting cells with non-ionic detergents such as Triton, we determined that ALPase is present in the cytoskeletal fraction in fully differentiated B lymphocytes, X63 myeloma cells and Sp2/O hybridoma cells. During the course of B-lymphocyte activation, the ALPase shifted from a soluble to a Triton-insoluble form. Changes in the phosphorylation of Triton-insoluble proteins with molecular weights of 120, 100, 90, 75, 34 and 31 kDa were detected, coinciding with the appearance of the ALPase in this fraction. The possible role of ALPase in the differentiation of B cells is discussed.

General Principles of Complex Biological Systems Operating in Immunology. Self-Responses Might Define the Boundaries of the Developing Immune System

There are two characteristics of the Immune System, common to complex biological systems, that have to be mentioned together, that is autonomy and death. Autonomy, from the Greek autos (self) and nomos (law) meaning literally “control of the self”, is provided by the recursive structure of the system. Death is a consequence of the entity’s being made of multiple parts. In death, these parts are disassembled or randomized and consequently result in the destruction of autonomy. However, if mere survival is the objective, then the harder rocks have to be placed near the top of the list as those most successful among macroscopic entities. Therefore, the simple tautology of natural selection, stated as those descriptive propositions which are true for the longest time remain true longer than those that become untrue sooner, needs to be taken into larger perspective. It is, in fact, possible that rocks resist change unchanging, while living things escape change by correcting change or by incorporating continual change into their own being (1). Stability may be achieved either by rigidity, by continual repetition or by some cycle of smaller changes through continuous return to a status quo ante (2).