CD4+CD25+ Regulatory T Cells: Origin, Function And Therapeutic Potential

The vertebrate immune system defends the organism against invading pathogens while at the same time being self-tolerant to the body's own constituentsthuspreservingitsintegrity. Multiplemechanismsactinconcert to ensure self-tolerance. During intrathymic development, the nascent T cell repertoire is purged from autoreactive T cells via negative selection, a process also known as recessive tolerance. Ridding of self-reactivity, however, isnotcomplete, asattestedbythepresenceofself-reactiveTcells intheperipheralTcellrepertoire. Hence, additionaltolerancemechanisms, collectively referred to as dominant tolerance, have been postulated on theoreticalgrounds(seethechapterbyA. Coutinhoetal. inthisvolume)and experimentalprooffortheirexistencehadbeenrepeatedlyclaimedinthepast 40years. Whilesomeoftheseclaims, largelybasedoninvitroexperiments, laterfellintodisrepute(i. e., theinfamousCD8suppressorcellsexpressingI-J molecules), concurrent, butlesswellpublicizedstringsofresearch, provided unremitting evidence for dominant tolerance mechanisms. These include the postnatal thymectomy model pioneered by Nishizuka and Sakakura in 1969, the dominant tolerance model in chicken and quail chimeras introducedbyleDouarinandcolleagues, andstudiesoninfectioustolerance by the Waldmann laboratory. A breakthrough in this ?eld was achieved by the identi?cation and isolation by Sakaguchi's and Shevach's groups of ] + aCD4 CD25 TcellsubsetexertingsuppressiononeffectorTcellsbothin vitroandinvivo. Thisinstigatedanavalancheofpublicationsonsuppressor Tcells. Whilelargelyoverlookedforsomanyyears, thereisnowhardlyany aspectofimmunitythatdoesnotseemtobeaffectedbysuppressorTcells. This volume will hardly be more than a snapshot in thisfast-moving ?eld, yetwehopethatitwillofferinspirationandorientationtothescientistwho wouldliketoenterthis?eld. To date, many different cells have been described that can suppress + + other cells of the immune system: CD4 CD25 regulatory T cells (Treg), + ? CD4 CD25 regulatory T cells, T regulatory 1 cells (Tr1), T-helper 3 cells + ? (Th3), CD8 CD28 Tcells, NKTcells, aswellastolerogenicdendriticcells. Suppressive CD4 T cells fall at least into two categories. So called natural VI Preface + + CD4 CD25 Tregformpartoftheintra-thymicallyselectedTcellrepertoire andapparentlyconstituteadistinctlineage. Incontrast,"adaptive"regulatory Tcellsareinstructedintheperipherytobecomesuppressivecells, theyform + + amoreheterogeneousgroupincludingCD4 CD25 Treg, Tr1, andTh3cells. As natural Treg are so far the best characterized entity, the ?rst three contributionsofthisvolume(C. Cozzoetal., C. -S. Hsiehetal., andL.

The vertebrate immune system defends the organism against invading pathogens while at the same time being self-tolerant to the body’s own constituents thus preserving its integrity. Multiple mechanisms work in concert to ensure self-tolerance. Apart from purging the T cell repertoire from auto-reactive T cells via negative selection in the thymus dominant tolerance exerted by regulatory T cells plays a major role in tolerance imposition and maintenance. Among the various regulatory/suppressive cells hitherto described, CD4⁺CD25⁺ regulatory T cells (Treg) and interleukin-10 producing T regulatory 1 (Tr1) cells have been studied in most detail and are the subject of most articles in this issue. Treg, also called "natural" regulatory T cells, will be traced from their intra-thymic origin to the site of their action in peripheral lymphoid organs and tissues.

The repertoire of Treg is clearly biased towards recognition of self-antigens, thereby potentially preventing autoimmune diseases such as gastritis and oophoritis. Regulatory T cells, however also control infections, allergies and tolerance to transplanted tissues and this requires their induction in the periphery under conditions which are not yet fully understood. The concept of dominant tolerance, by far not novel, will offer new insights and hopefully tools for the successful treatment of autoimmune diseases, improved cancer immunotherapy and transplant survival. The fulfillment of these high expectations will, however, require their unambiguous identification and a better understanding of their mode of action.