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Females are more susceptible than males to many autoimmune diseases. The processes causing this phenomenon are incompletely understood. Here, we demonstrate that aged female mice acquire a previously uncharacterized population of B cells that we call age-associated B cells (ABCs) and that these cells express integrin ␣ X chain (CD11c). This unexpected population also appears in young lupus-

Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder with familial and acquired forms. The familial form is associated with mutations in the perforin gene and both forms are associated with severe defects in lymphocyte cytotoxic function. We examined perforin-deficient mice as a model of HLH in order to gain insight into this poorly understood disorder. While these mice do not spontaneously develop HLH-like symptoms, we found that they manifest all of the features of HLH after infection with lymphocytic choriomeningitic virus (LCMV). Following LCMV infection, perforin-deficient mice develop fever, splenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, and elevation of multiple serum cytokine levels, and hemophagocytosis is evident in many tissues. Investigation into how this phenotype develops has revealed that CD8 ؉ T cells, but not natural killer (NK) cells, are necessary for the development of this disorder. Cytokine neutralization studies have revealed that interferon gamma (IFN␥) is uniquely essential as well. Finally, the excessive amount of IFN␥ seen in affected mice appears to be driven by increased antigen presentation to CD8 ؉ T cells. These studies provide insight into the pathophysiology of HLH, and provide new targets for specific therapeutic intervention in this fatal disorder. IntroductionHemophagocytic lymphohistiocytosis (HLH) is a rare disorder with both familial and acquired forms. [1][2][3] Specific criteria for the diagnosis of this disorder have been established (Table 1). 4 As a familial disorder, it has an autosomal recessive inheritance and usually affects infants. As an acquired disorder, it is more variable and affects a wider age range. Acquired, or secondary, HLH has been associated with infection (most commonly with Epstein-Barr virus [EBV]), malignancy, and autoimmunity. Familial cases also commonly appear to be triggered by viral infection. While some of the features of HLH, including hemophagocytosis, can be seen in circumstances with significant immune activation, the diagnosis of this disorder is limited to situations where all of the diagnostic criteria are met.In addition to the diagnostic features listed in Table 1, patients with HLH variably display a number of other characteristic features, such as hepatomegaly, jaundice, adenopathy, rash, seizures, and focal neurologic deficits. When assayed, patients have been found to have strikingly high serum levels of numerous cytokines including interferon gamma (IFN␥), tumor necrosis factor ␣ (TNF-␣), interleukin 6 (IL-6), IL-10, and macrophagecolony-stimulating factor (M-CSF). [5][6][7][8][9] Histologic examination of lymphoid tissues reveals a mixed infiltrate of lymphocytes and macrophages that appear highly activated. Liver biopsies typically display periportal infiltrates composed of lymphocytes and macrophages. Bone marrow biopsies may variably reveal hypoplasia or aplasia. 1 Overall, patients with HLH appear to have striking activation of the immune system by both clinical and laboratory measures. It i...

Memory T cells maintain their numbers for long periods after antigen exposure. Here we show that CD8+ T cells of memory phenotype divide slowly in animals. This division requires interleukin-15 and is markedly increased by inhibition of interleukin-2 (IL-2). Therefore, the numbers of CD8+ memory T cells in animals are controlled by a balance between IL-15 and IL-2.

A modification of the polymerase chain reaction has been used to establish the fact that a collection of Staphylococcus aureus toxins are "superantigens," each of which interacts with the T-cell a4i receptor of human T cells by means of a specific set of V,8 elements.The antigen receptor [T-cell receptor (TCR)] on most peripheral T cells is a heterodimer made up of a and P chains. Five germ-line-encoded variable elements (Va, Ja, Vp, Dp, and JP) as well as non-germ-line-encoded amino acids contribute to the receptor combining site (1-4). The ligands for aB TCRs are combinations of antigen-derived peptides, bound to major histocompatibility complex proteins (MHC) (5)(6)(7)(8). Usually the specificity of TCRs for antigen plus MHC is determined by all of the variable elements of both a and p chains (1-4). Exceptions to this rule have, however, recently been documented by us and others (9-18). In the examples studied so far, the exceptions involve an antigen/MHC combination that can stimulate T cells bearing a particular VP, almost regardless of the composition of the rest of the receptor on these cells. We have suggested the term "superantigen" to describe receptor ligands of this type. These superantigens and the VP elements that engage them have been well documented in mice with the help of an increasing number of VP-specific antibodies and DNA probes.Some superantigens are endogenously synthesized-for example, a mouse B-cell-derived self-superantigen bound to IE reacts with nearly all T cells bearing Vl17a and mice that express IE delete nearly all V,817a' T cells (9, 10). Exogenous superantigens have also been described. We and others have recently shown that some bacterial proteins are also able to stimulate T cells in a Vp-specific fashion (15-19). For example, Staphylococcus aureus enterotoxin B (SEB) stimulates mouse T cells bearing Vp83, and has no effect on most other cells. Since the S. aureus toxins are important contributors to morbidity and mortality in man (20), we wished to extend our studies on bacterial superantigens to human T cells. In an initial study, we used monoclonal antibodies (mAbs) to four human VP elements to show that T cells expressing these VP elements were differentially stimulated by a panel of S. aureus toxins (18). However, since there are at least 20 V, families in human (2, 21), we were limited by the lack of a complete set of anti-VP mAbs. We have, therefore, modified the methodology of the polymerase chain reaction (PCR) (22,23) MATERIALS AND METHODSPreparation of RNA and cDNA Synthesis. Total RNA was prepared from anti-CD3-stimulated peripheral T cells as described (18,24). Two micrograms of total RNA was used for the synthesis of first strand cDNA using reverse transcriptase (Amersham) and random hexanucleotides. The reaction was stopped by heating for 5 min at 950C before PCR.Amplification of cDNA by PCR and Quantitation of Amplified Products. One-twentieth of each cDNA sample was coamplified using a Vp-specific primer with a C,3 primer and two Ca primers (Table 1...

The efficacy of vaccines depends on the presence of an adjuvant in conjunction with the antigen. Of these adjuvants, the ones that contain aluminium, which were first discovered empirically in 1926, are currently the most widely used. However, a detailed understanding of their mechanism of action has only started to be revealed. In this Timeline article, we briefly describe the initial discovery of aluminium adjuvants and discuss historically important advances. We also summarize recent progress in the field and discuss their implications and the remaining questions on how these adjuvants work.

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At the end of the T cell response, the majority of the activated T cells die. We activated Vbeta8(+) T cells with staphylococcal enterotoxin B (SEB) in vivo and monitored the expansion and deletion of Vbeta8(+) T cells. We found that, in response to SEB, activated T cells died in vivo in the absence of Fas or TNF-R signaling but not when they overexpressed human Bcl-2. We also found that Vbeta8(+) T cells from Bim-deficient mice are resistant to SEB-induced deletion. While Bim levels did not change, endogenous Bcl-2 levels within Vbeta8(+) T cells decrease following SEB injection. Thus, the death of superantigen-stimulated T cells in vivo is mediated by Bim and may be modulated by a decrease in Bcl-2.