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S. Pyogenes-Induced Inflammation
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and TNF-
, was higher from purified monocytes incubated with HBP plus M1 than with M1 alone; HBP alone had no effect. IL-6 release was reduced in the presence of anti-HBP Ab. M1 increased the number of CD25+ hamster cells transfected with human TLR2 in a dose-dependent manner. Incubation with HBP caused an increase in intracellular levels of free calcium in monocytes that was blocked by an anti-2-integrin mAb. An inhibitor of exocytosis caused an intracellular increase in the cytokines after M1 stimulation; HBP had no additional effect. Leakage of HBP and its uptake by monocytes/macrophages was demonstrated in the lesions from patients with necrotizing fasciitis or severe cellulitis caused by S. pyogenes. In the model presented by the authors, M protein has two roles: it stimulates HBP release from invading PMNs, and it cooperates with HBP in triggering TLR2 to induce monocytes to release proinflammatory cytokines. Chlamydia in Pregnancy
The common sexually transmitted bacterium, Chlamydia trachomatis, is associated with adverse outcomes in pregnancy. However, the molecular events responsible are not understood. As TLR2 and TLR4 are highly expressed in the female reproductive tract, Equils et al. (p. 1257
) looked at the apoptotic effects of C. trachomatis heat shock protein 60 (HSP60) on trophoblasts. HSP60 induced a high level of apoptosis in primary trophoblasts from early second trimester placentas and a lower level in a trophoblast cell line as assessed by propidium iodide and annexin V staining. Treatment of the trophoblast cell line with anti-TLR4, but not anti-TLR2 or anti-TNF-, mAb before stimulation blocked HSP60-induced apoptosis. Caspase-8, caspase-3, and caspase-9 were activated in the HSP60-treated trophoblasts; pretreatment with a pan-caspase inhibitor only partially blocked HSP60-induced apoptosis in the monocyte cell line but completely blocked it in primary fibroblasts from second trimester placentas. The authors demonstrate that C. trachomatis-induced early pregnancy loss is due to both caspase-dependent and caspase-independent apoptosis mediated via HSP60 stimulation of TLR4 on trophoblasts.
Ets-1 and CD8+ T Cell Development
Although several studies implicate the transcription factor Ets-1 in early pre-TCR-dependent stages of thymocyte development and peripheral lymphocyte function and homeostasis, a role for Ets-1 in thymocyte selection and lineage commitment has not been shown. Clements et al. (p. 905 ) detected a lower percentage of CD8 single-positive (SP) T cells and an increased percentage of double-positive (DP) immature thymocytes in thymii of mice homozygous for mutant Ets-1 (Ets-1p/p) compared with wild-type controls. Generation of CD4 SP thymocytes was comparable between mutant and wild-type mice. Only Ets-1p/p mice had DP thymocytes in their mature thymocyte population and increased percentages of double-negative cells in both mature and transitional populations. Despite a decreased percentage of CD8 SP thymocytes, CD8+ T cells expressing high levels of CD44 and CD86 and reduced levels of Thy1 were isolated from peripheral lymph nodes and spleens of Ets-1p/p mice. Thymocytes from female Ets-1p/p mice expressing an HY TCR had HY TCR expression on immature double-negative thymocytes equivalent to that of HY TCR Ets-1+/+ controls; a subset of mature mutant DP thymocytes expressed HY TCR at a high level. Defective generation of CD8 SP thymocytes occurred in Ets-1p/p cells in lethally irradiated wild-type mice given Ets-1p/p bone marrow with or without wild-type bone marrow. No alteration in expression of other transcription factors known to regulate thymic selection and/or lineage commitment was detected by RT-PCR on Ets-1p/p DP thymocytes. The authors conclude that Ets-1 is required for TCR-regulated positive selection and CD8 lineage commitment of mouse thymocytes at the DP stage.
TRAILing "Helpless" Memory CD8+ T Cells
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Boosting Antimelanoma CTLs
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-chains of defined length were detected among Melan-A peptide-specific CD28– CTLs, whereas CD28+ CTLs had polyclonal TCR repertoires. One clonotype existed 14 mo before immunotherapy in a nonlymphoid tissue with metastases and became dominant in blood and metastatic nonlymphoid tissue 2 mo before and through 28 mo of vaccinations. However, its frequency was reduced and restricted to blood samples at 43 mo of treatment. T cell clones bearing the dominant clonotype isolated at various time points efficiently killed patient-derived melanoma cell lines with high avidity and exhibited rapid and sustained loss of telomere repeats. Eventually the tumor became Melan-A Ag negative and disease progressed. The expansion of a dominant preexisting anti-Melan-A CTL clone by Melan-A peptide vaccination demonstrates that antitumor immunization can be as effective as antiviral immunization in stimulating specific CTL proliferation in melanoma patients. Positive Selection of Tregs
Self-reactive regulatory T cells (Tregs) are present in high numbers in the periphery. However, the process by which these cells are positively selected in the thymus is unclear. Ribot et al. (p. 1101
) injected allogeneic bone marrow into irradiated C57BL/6 (B6) or DBA/2 mice that express endogenous retroviral superantigens (sAg). Higher percentages of thymic CD25high Tregs and lower percentages of sAg-specific V3-, V5-, and V6-expressing CD25– and CD25high cells were detected among CD4+ T cells in DBA/2 chimeras compared with B6 controls lacking sAg expression. However, sAg-specific V3+ T cells were not deleted in DBA/2 radiation chimeras that received MHC-deficient DBA/2 bone marrow cells, and those mice had a higher percentage of Foxp3+CD25–, CD25int, and CD25high Tregs expressing sAg-specific V3, V5, and V6 than B6 controls. DBA/2 mice given bone marrow from a DBA/2 mouse strain in which dendritic cells present sAg deleted Treg cell precursors. The Foxp3–CD25int CD4 single-positive population was enriched in sAg-specific T cells in DBA/2 mice given MHC-deficient DBA/2 bone marrow. A different agonist ligand did not enhance positive selection of precursors for conventional T cells. The data demonstrate that expression of agonist ligands exclusively by thymic epithelium enhances development of self-reactive Treg precursors.
Defining Rat Spleen DC Subsets
Josien and collaborators have described three subsets of dendritic cells (DCs) in rat spleen: CD4+, CD4–, and a rat counterpart of human plasmacytoid DC (pDC). In a continuation of their studies, Hubert et al. (p. 1007
) determined that frequencies of the DC subsets were specific for a rat strain and that each subset had characteristic morphological features. All DC subsets expressed mRNAs for TLRs 1–10, but levels of expression varied among the subsets. TLR7 and 9 were highly expressed by pDCs, TLRs 1–3 and 10 were highly expressed by CD4– DCs, and TLRs 1–3 and 7 were highly expressed by CD4+ DCs. Expression of mRNA for nucleotide-binding oligomerization domain 2 (NOD2) protein was high only in CD4+ DCs. Survival of the DC populations in the presence of specific TLR ligands correlated with their TLR expression patterns. Spontaneous survival of CD4+ DCs was 30% compared with 10% for the other two subtypes, and only CD4+ DC up-regulated CD80 and CD86 during overnight culture. Triggering with relevant TLRs or NOD2 up-regulated CD80 and CD86 on CD4– DCs and pDCs and stimulated their ability to activate allogeneic CD4+ T cells. IL-6, TNF-, and type I IFN were produced by stimulated pDCs; CD4– and CD4+ DCs produced IL-10. CD4– DCs and pDCs produced higher amounts of IL-12p40 after stimulation than CD4+ DCs. The study shows that rat spleen DC subsets have strain-dependent frequencies but that their TLR and NOD2 expression profiles and cytokine production in response to ligands are subset-specific.
IgA Switching
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and a plasmid expressing the specific histone methyltransferase (HMT). Sµ-S plasmid switching did not occur in transfected mouse cells lacking inactivation-induced cytidine deaminase, the enzyme that initiates class switch recombination. Enzyme mutants lacking HMT activity did not enhance switching. LPS-activated splenic B cells from mice lacking the HMT had a 2-fold reduction in IgA switching compared with controls but exhibited normal switching to other Ig isotypes. Those B cells also exhibited reduced switch recombination of the transfected Sµ-S plasmid. Mice lacking the HMT had one-half the frequency of IgA-expressing B cells in their Peyer’s patches compared with wild-type animals, but their stimulated spleen cells had unrearranged germline transcript expression equal to wild-type mice. The authors speculate that the specific HMT interacts with another repressor with specificity for acceptor S sequences. Summaries written by Dorothy L. Buchhagen, Ph.D.
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