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B cell survival during anti-CD20 mAb immunotherapy
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–/– mice. Anti-CD20 mAb treatment led to loss of splenic follicles and almost all of the mature and marginal zone B cells along with transitional T1 and T2 cells; spleen B1a cells were reduced by 70%. Peritoneal B1a, B1b, and B2 cells from mAb-treated mice bound mAb, but their numbers were not reduced until after 28–58 days of treatment. Anti-CD20 mAb treatment did not accelerate depletion of peritoneal CFSE-labeled wild-type or CD20–/– B2 cells introduced into wild-type mice 2–7 days earlier; CFSE-labeled wild-type, but not CD20–/–, B cells that had migrated to the spleen were eliminated almost completely by 7 days after treatment. Intraperitoneal injection of thioglycolate into wild-type mice 1 day before anti-CD20 mAb treatment resulted in a 65% reduction in B2 cell numbers in the peritoneum at day 2 compared with control animals; B1a and B1b cells were deleted by day 7 after treatment. Thioglycolate treatment had no effect in FcR–/– mice. The data suggest that the peritoneal cavity is a protective niche in which B cells evade FcR-dependent immune destruction during anti-CD20 mAb therapy. Identifying autoreactive CD4+ T cells
The pathology of most autoimmune diseases is mediated by CD4+ T cells that recognize self peptides. Yet details regarding the development of the autoantigen-specific T cells and their role in the autoimmune process are not available. Latham et al. (p. 3978 ) developed a chimeric HLA-DR1 recombinant molecule carrying a collagen II (CII) peptide (DR1-CII) that bound to a CII-specific TCR. DR1-CII tetramers stained CD4+ T cells from lymph nodes of DR1-transgenic mice immunized 10 days earlier with CII to elicit collagen-induced arthritis (CIA). A small population of tetramer-positive cells (1% of CD4+ T cells) was identified and expanded 10-fold by 4 days of stimulation ex vivo with a specific CII peptide. Most of the stimulated tetramer-positive cells expressed the TCR BV13 or BV8 gene segments used by CII peptide-specific DR1-restricted T cell hybridomas. Five days after immunization of DR1 mice with CII, CII peptide-specific cells were detected ex vivo among draining lymph node T cells; cell numbers peaked at 10 days but were still detectable at 130 days. Surface expression of CD62L decreased after day 5, whereas expression of CD44 and CD69 increased. Sorted tetramer-positive cells had higher levels of inflammatory and Th1 cytokine transcripts as measured by real-time PCR. Approximately 74% of CD4+ T cells from joint synovial tissues of mice with CIA expressed BV8 or BV14, and >74% of them bound tetramer. These studies demonstrate that autoimmune T cells that develop in lymph nodes and accumulate in arthritic joints of mice with CIA can be detected by a tetramer-based, ex vivo approach.
TLR9 and bacterial immunomodulation
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and a 1000-fold increase in serum IFN- at 1 h and 4 h, respectively, after i.v. challenge with LPS, other bacteria, or their components; no elevation in the cytokine levels was seen in similarly treated TLR9–/– animals. Priming with three other pathogenic agents induced strong LPS hypersensitivity in both wild-type and TLR9–/– mice. Whereas wild-type mice had increased splenic expression of IFN- mRNA at day 7 following P. acnes priming compared with treated TLR9-deficient mice, both mouse strains had enhanced TNF- mRNA expression within 1 h of injection with bacteria. All P. acnes-primed wild-type mice survived a challenge with live Salmonella enterica serovar typhimurium, but all challenged P. acnes-treated TLR9–/– mice were terminally ill by day 6. The authors conclude that IFN-, released after P. acnes interacts with TLR9, is responsible for the bacterial-induced immunomodulatory effects. CD4+ Th cells cross-prime CTL
Memory CD8+ CTL are generated with the participation of CD4+ Th lymphocytes. Although professional APCs are involved in CTL activation, the ability of helper T cells to act as APCs has not been demonstrated. Kennedy et al. (p. 3967
) pulsed conventional APCs with an immunodominant OVA peptide that bound to MHC class I molecule Kb. Complexes of OVA peptide with Kb, or with a Kb mutant that retained Kb function but could be distinguished from Kb, were detected on H-2b, H-2d, and H-2b/H-2d TCR-transgenic Th lines in the absence of peptide. The predominant complexes on resting or naive Th cells included both acquired and endogenous Kb/OVA peptide, whereas those on Th blasts were predominantly acquired Kb mutant/OVA peptide. Generation of MHC class I/OVA peptide complexes on the Th cells was greater with the OVA peptide covalently linked to a Th epitope (OVA/Th peptide) than with OVA peptide linked to a different I-Ab-restricted Th epitope from OVA. Approximately 35% of draining lymph node cells from TCR-transgenic mice injected with the OVA/Th peptide expressed Kb/OVA peptide complexes. Activated Th cells, incubated with Kb-negative APC loaded with OVA or OVA/Th peptide, were required to induce IFN- production in preactivated TCR-transgenic CTL in the presence of the appropriate peptide. T cell hybridoma cells specific for an MHC class II-restricted Th OVA epitope activated naive TCR-transgenic CTL in the presence of OVA and DC from K–/–D–/– mice. OVA peptide-activated Th cells were as effective as DC in stimulating the CTL and induced high levels of T cell activation markers and functions characteristic of central memory cells. Naive TCR-transgenic cells adoptively transferred into sublethally irradiated wild-type mice proliferated after peptide vaccination and persisted for longer than 10 wk. The authors propose that Th cells act as APC to present MHC class I-restricted epitopes to naive cells to generate central memory CTL.
Kinase regulation of autoimmunity
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40% of levels detected in healthy individuals. GRK2 levels in RR-MS patients in remission were lower than in patients with active RR-MS, in stroke patients with no autoimmunity or in healthy controls. All cell types were affected equally. Heterozygous GRK2 mice had a 50% reduction in GRK2 protein compared with wild-type littermates. Experimental autoimmune encephalomyelitis (EAE) induced in the GRK2+/– mice developed earlier, was not relapsing, and decreased over time. Numbers of infiltrated CD3+ T cells and activated macrophages and microglia were higher in spinal cords of GRK2+/– mice on day 13 after induction of EAE than in wild-type animals. The inflammatory infiltrates disappeared by day 45 after EAE induction in GRK2+/– mice that had become disease-free. Splenocytes from GRK2 heterozygotes and wild-type mice at day 48 postimmunization had similar in vitro proliferative responses and cytokine production when stimulated with the immunizing peptide. The authors conclude that down-regulation of GRK2 expression contributes to disease remission in MS patients and to less severe EAE in mice. C5 deficiency via exon skipping
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Treg depletion in HIV infection
T cell activation in chronically infected HIV patients is a predictor of disease progression and death. Although CD4+CD25+CD62L+ regulatory T cells (Tregs) inhibit activation of both CD4+ and CD8+ T cells, their numbers in HIV patients have not been determined. Eggena et al. (p. 4407 ) confirmed that Tregs (CD4+CD25brightCD62Lbright), purified by cell sorting from 81 untreated HIV-positive patients at a clinic in Uganda, suppressed anti-CD3-induced proliferation of CD4+CD25–CD62Lbright T responder cells. The percentage of Tregs in 25 HIV-negative Ugandans was 2.8%. Treg numbers in HIV patients were expressed in several different ways: as an absolute number or as ratios of CD4+, CD8+, or CD3+ cells. Although the numbers varied widely among patients, there was significant correlation between decline in absolute CD4+ T cells and decline in absolute Tregs. Tregs decreased as HIV disease progressed. HIV-positive individuals had increases of 31 and 63% for CD4+ and CD8+ T cell activation, respectively, that were negatively associated with CD4+ T cell count and positively associated with viral load. HIV-negative controls had activation levels of 5% for CD4+ T cells and 13% for CD8+ T cells. The results of the study suggest that Treg depletion results in activation of CD4+ and CD8+ T cells in HIV-infected hosts and directly contributes to AIDS mortality.
Summaries written by Dorothy L. Buchhagen, Ph.D.
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