Regulatory T cells engage in the maintenance of immunological self-tolerance by actively suppressing self-reactive lymphocytes. Little is known, however, about the molecular mechanism of their development. Here we show that Foxp3, which encodes a transcription factor that is genetically defective in an autoimmune and inflammatory syndrome in humans and mice, is specifically expressed in naturally arising CD4+ regulatory T cells. Furthermore, retroviral gene transfer of Foxp3 converts naive T cells toward a regulatory T cell phenotype similar to that of naturally occurring CD4+ regulatory T cells. Thus, Foxp3 is a key regulatory gene for the development of regulatory T cells.

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Control of Regulatory T Cell Development by the Transcription Factor Foxp3

Effector functions in the immune system are carried out by a variety of cell types, and as our understanding of the complexity of the system expands, the number of recognized subdivisions of cell types also continues to increase. B lymphocytes, producing antibody, were initially distinguished from T lymphocytes, which provide help for B cells (1, 2). The T-cell population was further divided when surface markers allowed separation of helper cells from cytotoxic cells (3). Although there were persistent reports of heterogeneity in the helper T-cell compartment (reviewed below), only relatively recently were distinct types of helper cells resolved. In this review we describe the differences between two types of cloned helper T cells, defined primarily by differences in the pattern of lymphokines ynthesized, and we also discuss the different functions of the two types of cells and their lymphokines. Patterns of lymphokine synthesis are convenient and explicit markers to describe T-cell subclass differences, and evidence increases that many of the functions of helper T cells are predicted by the functions of the lymphokines that they synthesize after activation by antigen and presenting cells. The separation of many mouse helper T-cell clones into these two distinct types is now well established, but their origin in normal T-cell populations is still not clear. Further divisions of helper T cells may have to be recognized before a complete picture of helper T-cell function can be obtained.

TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties.

In multicellular organisms, homeostasis is maintained through a balance between cell proliferation and cell death. Although much is known about the control of cell proliferation, less is known about the control of cell death. Physiologic cell death occurs primarily through an evolutionarily conserved form of cell suicide termed apoptosis. The decision of a cell to undergo apoptosis can be influenced by a wide variety of regulatory stimuli. Recent evidence suggests that alterations in cell survival contribute to the pathogenesis of a number of human diseases, including cancer, viral infections, autoimmune diseases, neurodegenerative disorders, and AIDS (acquired immunodeficiency syndrome). Treatments designed to specifically alter the apoptotic threshold may have the potential to change the natural progression of some of these diseases.

https://science.sciencemag.org/content/sci/267/5203/1456.full.pdf

Apoptosis in the pathogenesis and treatment of disease

Naive T lymphocytes travel to T-cell areas of secondary lymphoid organs in search of antigen presented by dendritic cells. Once activated, they proliferate vigorously, generating effector cells that can migrate to B-cell areas or to inflamed tissues. A fraction of primed T lymphocytes persists as circulating memory cells that can confer protection and give, upon secondary challenge, a qualitatively different and quantitatively enhanced response. The nature of the cells that mediate the different facets of immunological memory remains unresolved. Here we show that expression of CCR7, a chemokine receptor that controls homing to secondary lymphoid organs, divides human memory T cells into two functionally distinct subsets. CCR7- memory cells express receptors for migration to inflamed tissues and display immediate effector function. In contrast, CCR7+ memory cells express lymph-node homing receptors and lack immediate effector function, but efficiently stimulate dendritic cells and differentiate into CCR7- effector cells upon secondary stimulation. The CCR7+ and CCR7- T cells, which we have named central memory (TCM) and effector memory (TEM), differentiate in a step-wise fashion from naive T cells, persist for years after immunization and allow a division of labour in the memory response.

Two subsets of memory T lymphocytes with distinct homing potentials and effector functions

Apoptosis by death factor.

Immunological Synapse CD28 Signals in the Immature

71P Aromatase inhibitors and fracture prevention: Is our current approach correct?

Immune response to myeloma cells and idiotypes.

The immune system is effective at fighting a vast diversity of microbes and eliminating toxic substances. In contrast to most other organ systems, the total number of immune cells can increase is often attributalbe to a 1000- to 50,000-fold expansion of the lymphocytes specific for the antigens of the microbe. At the same time, the immune system continuously generates new lymphocytes, each specific for a different antigen, in the hope that one or more of these will prove useful against future infections. In the face of this massive production of cells, the immune system has developed mechanisms to eliminate lymphocytes, so that it can maintain an optimal size and a balanced representation of cells. These mechanisms rely on an event called programmed cell death, or apoptosis.

Role of T Cell Death and Cytokines in Autoimmunity

The immune system responds to invaders (pathogenic microbes and cancer cells) but is tightly controlled to prevent harmful reactions against self tissues, commensal microbes, and the fetus. Elucidation of the molecular basis of these control mechanisms has been one of the most impressive recent advances in Immunology. Two of these mechanisms are particularly important and are being targeted therapeutically - inhibitory receptors (so-called checkpoint molecules) and a population of CD4+ T cells called regulatory T cells. This article summarizes how defining these mechanisms has opened new avenues for therapeutic manipulation of immune responses, and how experimental models, including transgenic and knockout mice we and others have used, have contributed to developing the critical knowledge base.

Abul K. Abbas

Papers

Immunological Synapse CD28 Signals in the Immature

71P Aromatase inhibitors and fracture prevention: Is our current approach correct?

Immune response to myeloma cells and idiotypes.

Role of T Cell Death and Cytokines in Autoimmunity

Harnessing the immune response: basic principles and therapeutic applications.