It is known that T cells engage antigen-presenting cells (APCs) in a stable interaction that results in sustained TCR signaling. We show here that the duration of this process is critical in determining whether T cells will be activated or deleted. Whereas naive T cells require approximately 20 hr of sustained signaling to be committed to proliferation, effector T cells become committed after only 1 hr but die following activation if antigenic stimulation is prolonged. Costimulation by anti-CD28 facilitates T cell activation by decreasing the time of commitment and by protecting T cells from death. These findings explain in quantitative terms the essential requirement for professional APCs in T cell priming and show that the duration of antigenic stimulation is the major factor determining the fate of naive and effector T cells.

Macrophages are one of the most diverse cell populations in terms of their anatomical location and functional specialization during both homeostasis and disease. Although it has been shown in different fate mapping models that some macrophages present in adult tissues are already established during fetal development, their exact origins are still under debate. In the current study, we developed a fate mapping strain, based on the Kit locus, which allowed us to readdress "the origins" question. Different types of macrophages from various adult tissues were traced to their fetal or adult sources by inducing labeling in precursors at several time points either during fetal development or in adult mice. We show that all adult macrophages, resident or infiltrating, are progenies of classical hematopoietic stem cells (HSC) with the exception of microglia and, partially epidermal Langerhans cells, which are yolk sac (YS)-derived.

SummaryWe describe mice that express a transgenic T cell receptor o~/B (TCR-o~/B) specific for peptide 111-119 from influenza hemagglutinin presented by I-E a class II major histocompatibility complex (MHC) molecules. The transgenic TCR is expressed on CD4 +8-as well as CD4-8 + mature T cells even in mice that are deficient in rearrangement or do not express endogenous TCR.-ol genes. The CD4-8 + T cells require I-E a class II MHC molecules for positive selection and can be activated to proliferate and to kill by I-E a molecules presenting the relevant peptide. Full maturation of these cells, however, also requires the presence of class I MHC molecules. The results are compatible with the notion that T cell maturation requires multiple receptor-ligand interactions and establish an exception to the rule that class II-restricted TCRs are exclusively expressed by mature CD4+8-cells.

It is well established that lymphoid dendritic cells (DC) play an important role in the immune system. Beside their role as potent inducers of primary T cell responses, DC seem to play a crucial part as major histocompatibility complex (MHC) class II+ “interdigitating cells” in the thymus during thymocyte development. Thymic DC have been implicated in tolerance induction and also by some authors in inducing major histocompatibility complex restriction of thymocytes. Most of our knowledge about thymic DC was obtained using highly invasive and manipulatory experimental protocols such as thymus reaggregation cultures, suspension cultures, thymus grafting, and bone marrow reconstitution experiments. The DC used in those studies had to go through extensive isolation procedures or were cultured with recombinant growth factors. Since the functions of DC after these in vitro manipulations have been reported to be not identical to those of DC in vivo, we intended to establish a system that would allow us to investigate DC function avoiding artificial interferences due to handling. Here we present a transgenic mouse model in which we targeted gene expression specifically to DC. Using the CD11c promoter we expressed MHC class II I-E molecules specifically on DC of all tissues, but not on other cell types. We report that I-E expression on thymic DC is sufficient to negatively select I-E reactive CD4+ T cells, and to a less complete extent, CD8+ T cells. In contrast, if only DC expressed I-E in a class II–deficient background, positive selection of CD4+ T cells could not be observed. Thus negative, but not positive, selection events can be induced by DC in vivo.

Superantigens (SAgs) are viral or bacterial proteins that act as potent T-cell stimulants and have been implicated in a number of human diseases, including toxic shock syndrome, diabetes mellitus and multiple sclerosis. The interaction of SAgs with the T-cell receptor (TCR) and major histocompatibility complex (MHC) proteins results in the stimulation of a disproportionately large fraction of the T-cell population. We report here the crystal structures of the beta-chain of a TCR complexed with the Staphylococcus aureus enterotoxins C2 and C3 (SEC2, SEC3). These enterotoxins, which cause both toxic shock and food poisoning, bind in an identical way to the TCR beta-chain. The complementarity-determining region 2 (CDR2) of the beta-chain and, to lesser extents, CDR1 and hypervariable region 4 (HV4), bind in a cleft between the two domains of the SAgs. Thus, there is considerable overlap between the SAg-binding site and the peptide/MHC-binding sites of the TCR. A model of a TCR-SAg-MHC complex constructed from the crystal structures of (1) the beta-chain-SEC3 complex, (2) a complex between staphylococcal enterotoxin B (SEB) and an MHC molecule, and (3) a TCR V(alpha) domain, reveals that the SAg acts as a wedge between the TCR and MHC to displace the antigenic peptide away from the TCR combining site. In this way, the SAg is able to circumvent the normal mechanism for T-cell activation by specific peptide/MHC complexes.

IL-17-committed γδ T (γδT17) cells participate in many immune responses but their developmental requirements and subset specific functions remain poorly understood. Here we report that a commonly used CD45.1+ congenic C57BL/6 mouse substrain is characterized by a selective deficiency in Vγ4+ γδT17 cells. This trait is due to a spontaneous mutation in the transcription factor Sox13 that causes an intrinsic defect in development of these cells in the neonatal thymus. γδT17 cells migrate at low rates from skin to lymph nodes. In a model of psoriasis-like dermatitis, Vγ4+ γδT17 cells expand markedly in lymph nodes and home to inflamed skin. Sox13 mutant mice are protected from psoriasis-like skin changes, identifying a role for Sox13-dependent γδT17 cells in this inflammatory condition.

A study of the organization of light- and heavy-chain immunoglobulin genes in mouse splenic B cells, spleen-derived hybridomas and plasmacytomas has unequivocally demonstrated that aberrant rearrangements are common during normal B-cell development. The results support a probabilistic model for allelic exclusion of immunoglobulin gene expression.

Superantigens (SAGs) are a class of immunostimulatory proteins of bacterial or viral origin that activate T cells by binding to the V beta domain of the T cell antigen receptor (TCR). The three-dimensional structure of the complex between a TCR beta chain (mouse V beta8.2) and the SAG staphylococcal enterotoxin B (SEB) at 2.4 A resolution reveals why SEB recognizes only certain V beta families, as well as why only certain SAGs bind mouse V beta8.2. Models of the TCR-SEB-peptide/MHC class II complex indicate that V alpha interacts with the MHC beta chain in the TCR-SAG-MHC complex. The extent of the interaction is variable and is largely determined by the geometry of V alpha/V beta domain association. This variability can account for the preferential expression of certain V alpha regions among T cells reactive with SEB.