Microglia are crucial for immune responses in the brain. Although their origin from the yolk sac has been recognized for some time, their precise precursors and the transcription program that is used are not known. We found that mouse microglia were derived from primitive c-kit(+) erythromyeloid precursors that were detected in the yolk sac as early as 8 d post conception. These precursors developed into CD45(+) c-kit(lo) CX(3)CR1(-) immature (A1) cells and matured into CD45(+) c-kit(-) CX(3)CR1(+) (A2) cells, as evidenced by the downregulation of CD31 and concomitant upregulation of F4/80 and macrophage colony stimulating factor receptor (MCSF-R). Proliferating A2 cells became microglia and invaded the developing brain using specific matrix metalloproteinases. Notably, microgliogenesis was not only dependent on the transcription factor Pu.1 (also known as Sfpi), but also required Irf8, which was vital for the development of the A2 population, whereas Myb, Id2, Batf3 and Klf4 were not required. Our data provide cellular and molecular insights into the origin and development of microglia.

Lack of immunological tolerance against self-antigens results in autoimmune disorders. During onset of autoimmunity, dendritic cells (DCs) are thought to be critical for priming of self-reactive T cells that have escaped tolerance induction. However, because DCs can also induce T cell tolerance, it remains unclear whether DCs are required under steady-state conditions to prevent autoimmunity. To address this question, we crossed CD11c-Cre mice with mice that express diphtheria toxin A (DTA) under the control of a loxP-flanked neomycin resistance (neoR) cassette from the ROSA26 locus. Cre-mediated removal of the neoR cassette leads to DTA expression and constitutive loss of conventional DCs, plasmacytoid DCs, and Langerhans cells. These DC-depleted (ΔDC) mice showed increased frequencies of CD4 single-positive thymocytes and infiltration of CD4 T cells into peripheral tissues. They developed spontaneous autoimmunity characterized by reduced body weight, splenomegaly, autoantibody formation, neutrophilia, high numbers of Th1 and Th17 cells, and inflammatory bowel disease. Pathology could be induced by reconstitution of wild-type (WT) mice with bone marrow (BM) from ΔDC mice, whereas mixed BM chimeras that received BM from ΔDC and WT mice remained healthy. This demonstrates that DCs play an essential role to protect against fatal autoimmunity under steady-state conditions.

SummaryReeent studies have demonstrated that the CD3-~ subunlt of the T eell antigen reeeptor (TCR) eomplex Is involved In signal transduetlon. However, the funetlon of the remalnlng Invariant subunits, CD3-y, -ö, and e, Is still poorly understood. To examine thelr role In TCR funetlon, we have eonstrueted TCR/CD3 eomplexes devold of tunetlonal ~ subunlt and showed that they are still able to trigger the produellon of Interleukln-2 in response to antigen or superantigen. These data, together with previous results, Indleate that the TCR/ CD3 eomplex Is eomposed of at least two parallel Iransduelng unlts, made 01 the YÖE and ~ ehalns, respeetlvely, Furthermore, the analysis 01 partially truneated ~ ehains has led us to Indlvlduallze a lunetlonal domaln that may have eonstltuted the buildlng block of most of the transduelng subunlts assoelated wlth antigen reeeptors and some Fe receptors. IntroduetionThe T cell antigen receptor (TCR) is a multisubunit complex composed of the products of at least six distinct genes. The TCR a and TCR ß subunits exist as disulfidelinked heterodimers, possess short cytoplasmic tails, and contain clonally variable regions that determine the antigenic specificity of the complex. The remaining subunits, termed CD3-y, -ö, -E, -~, and -1], are invariant, noncovalently associated with the TCR aß dimer, and possess large intracytoplasmic domains thought to be responsible for coupling antigen recognition to various signal transductlon pathways. The evolutionarily related y, Ö, and e subunits are expressed as noncovalently associated ye and OE pairs (Koning et al., 1990;Blumberg et al. , 1990; De la Herra et al. , 1991), and display immunoglobulin-like extracellular domains (Gold et al., 1987). In contrast, the ~ and 1] subunlts contaln an extracellular domain of only 9 residues and constitute the prototype of a new protein family that includes the y chain of the high affinity IgE receptor (FceRI)