Regulatory T Cells: Historical Perspective

3 The innate immune system, the earliest evolutionry form of defense against pathogens, provides a road, relatively nonspecific form of immunity. In ontrast, the adaptive immune system provides an fficient and specific line of defense against unique athogens. Somatic cell rearrangements of their antien-specific receptors provides essentially unlimited pecificities, which are important given the high freuency of mutations found in infectious organisms. hese specificities are predetermined and generated efore encounters with antigens. This diversity is a critical component in our ability o defend against the myriad of potential pathogens. n the other hand, however, it poses a threat of utoimmune disease, especially due to the major hisocompatibility complex (MHC)-restricted T-cell recgnition. This need for balance was recognized by P. hrlich in 1910, when he noted the need for a welldapted regulatory contrivance and stated that “horor autotoxicus” would result without a balancing orce [1]. For a particular T cell to develop, it must express ntigen receptors that interact with self-peptide– HC complexes. The T-cell repertoire is shaped by oth positive and negative selection in the thymus. he developing T cells, each with a different T-cell eceptor (TCR), undergo a positive selection step in hich only T cells that can interact with the MHC urvive. This is followed by a negative selection step in hich T cells with high avidity for self-MHC are eleted, preventing autoimmunity. Therefore, T cells hat can interact with MHC with only low avidity urvive and migrate out to the periphery. The binding f pathogenic peptides to the MHC molecule leads to igh-avidity interactions with the TCR and results in -cell activation. Although this receptor editing is ssential for survival of the organism (to prevent auoimmunity), it is imperfect at times, allowing autorective T cells to enter the peripheral blood. Because utoimmune diseases are not rampant, there must be a echanism of tolerance induction that is fairly effecive. Detection of cell surface markers for T cells in the 970s described a population of these cells that exert heir suppressive effects through antigen-specific facors and indicated that this immune suppression was inked to a specific region of the MHC, designated as -J [2]. However, the lack of molecular or biochemical haracterization of these factors and, with the seuencing of the MHC, the lack of a defined I-J region ed to the demise of the entire field in the 1980s. onetheless, the research provided clear clues that opulations of such cells exist and indicated their mportance to overall homeostasis. Over the past sevral decades, multiple experimental models have demnstrated the dominant immune suppression that is ritical to preventing the development of autoimmune isease. Several investigators persevered through these difcult times; their efforts, along with advances in the efinition of subpopulations of CD4 T cells, has led o a renaissance of this field. Sakaguchi et al. [3] elped rekindle interest by demonstrating that a small opulation of naturally occurring CD4 T cells (aproximately 10%) co-expressing the interleukin-2 reeptor (IL-2R)chain (CD25) is necessary to the ontrol of autoreactive cells in vivo. These cells are nown to be hyporesponsive and suppressive in naure. They have been described in both murine modls and in human disease and have been termed “reglatory T cells.” This term avoids the stigma ssociated with the term “suppressor T cells” and is robably a better description of these cells’ functional ctivity.