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1223 J. Exp. Med. ? The R ockefeller University Press • 0022-1007/97/10/1223/10 $2.00Volume 186, Number 8, October 20, 1997 1223–1232http://www.jem.org Survival of Mature CD4 T Lymphocytes Is Dependent on Major Histocompatibility Complex Class II–expressing Dendritic Cells By Thomas Brocker From the Basel Institute for Immunology, CH-4005 Basel, Switzerland Summary Thymic T cell development is controlled by T cell receptor (TCR )–major histocompatibilitycomplex (MHC) interactions, whereas a further dependence of peripheral mature T cells onTCR –MHC contact has not been described so far. To study this question, CD4 T cell survivalwas surveyed in mice lacking MHC class II expression and in mice expressing MHC class IIexclusively on dendritic cells. Since neither of these mice positively select CD4 T cells in thethymus, they were grafted with MHC class II–positive embryonic thymic tissue, which hadbeen depleted of bone marrow derived cells. Although the thymus grafts in both hosts were re-populated with host origin thymocytes of identical phenotype and numbers, an accumulationof CD4 1 T cells in peripheral lymphoid organs could only be observed in mice expressingMHC class II on dendritic cells, but not in mice that were completely MHC class II deficient.As assessed by histology, the accumulating peripheral CD4 T cells were found to be in closecontact with MHC class II 1 dendritic cells, suggesting that CD4 T cells need peripheral MHCclass II expression for survival and that class II 1 dendritic cells might play an important role forthe longevity of CD4 T cells. T hymic positive selection is a process that generates ma-ture CD4 1 and CD8 1 single-positive T lymphocytesfrom CD4 1 CD8 1 double-positive thymocytes. The mech-anistic control of positive selection is the interaction be-tween TCR on thymocytes and MHC-encoded moleculeson thymic epithelial cells. Mature CD4 1 and CD8 1 single-positive thymocytes, selected on MHC class II and I, respec-tively, subsequently leave the thymus and seed the peripherallymphoid organs (1–3). Consequently, CD4 1 single-posi-tive thymocytes and CD4 1 peripheral T cells are nearlyabsent in class II–deficient mice (4, 5).The further survival of peripheral T cells seems not to bedependent on antigen-specific TCR –MHC interactions.Transfer experiments performed with T cells from TCR -transgenic mice in the presence or absence of antigen (6, 7)showed that specific Ag is not necessary for T cell survival.In another experimental model, Sprent et al. (8) demon-strated that when unseparated lymph node cell suspensionswere injected into H-2 identical SCID hosts, they formed aself-sufficient pool of lymphocytes. T cells survived in thissystem without reduction in numbers in the absence of an-tigen. However, conflicting results have been reported onthe survival of T cells in the absence of MHC moleculesexpressed on hematopoietic cells. When irradiated normalmice received bone marrow from class II–deficient mice,normal CD4 T cell repopulation was observed in one study(9). Others doing the same experiment could not detect re-constitution of the CD4 compartment in the MHC classII–negative environment of such mice (10). Huss et al.speculated that this discrepancy could have been caused bythe different time spans of bone marrow inoculum in thehost mice used by the two groups or different bone mar-row treatments (e.g., T cell depletion) before injection(10). Therefore, these experiments could not definitelyclarify the question of whether peripheral CD4 T cell sur-vival is dependent of peripheral MHC class II expression.In a recent report, Takeda et al. (11) transplanted untreatedfetal thymi from MHC class II 1 mice under the kidneycapsules of class II 1 , as well as class II–deficient, hosts. Theauthors observed an identical initial donor type CD4 1 Tcell accumulation in the periphery of both hosts. In com-parison to the MHC class II 1 mice, the class II–deficienthosts showed faster declining numbers of peripheral CD4 1 T cells. These results suggested that interactions betweenCD4 1 T cells and MHC class II 1 peripheral cells are notnecessary for short-term survival, but might be importantfor longevity of T cells. However, a potential contamina-tion of the MHC class II–deficient peripheral organs of thehosts with MHC class II 1 donor type cells originating fromthe transplanted thymi (thymic dendritic cells, B cells, mac-