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IN THIS ISSUE

ATRA Induces Gut-Homing Treg Cells

Natural and induced FoxP3⁺CD4⁺CD25⁺ regulatory T (Treg) cells influence the activities of immune cells in lymphoid and nonlymphoid tissues. Although Treg cells are found in the intestinal mucosa in mice and humans, their origin is unknown. Kang et al. (p. 3724 ) induced FoxP3 mRNA and nuclear protein expression in naive CD4⁺CD25^– T cells from human cord blood by treatment with the vitamin A metabolite all-trans-retinoic acid (ATRA). Optimal induction required CD28 plus CD3 activation and IL-2. ATRA-induced histone acetylation of the FoxP3 gene promoter was detected by chromatin immunoprecipitation assays. Retinoic acid receptors RAR, , and were up-regulated by ATRA treatment, but only an RAR-specific antagonist blocked FoxP3 protein induction. ATRA-treated T cells suppressed proliferation of CD4⁺CD25^– T cells in vitro and expressed high levels of granzyme A. The ATRA-induced Treg cells expressed high levels of the mucosal tissue homing receptors CCR9 and integrin ₇ and were responsive to the CCR9 ligand CCL25. ATRA induced FoxP3⁺ mouse spleen cells only in the presence of TGF-1 but suppressed the generation of inflammatory Th17 cells. Mouse intestinal, but not spleen, dendritic cells induced CCR9⁺FoxP3⁺ T cells. Adoptively transferred OVA-specific FoxP3^– T cells were converted in vivo into FoxP3⁺ T cells in animals injected with OVA and given repeated s.c. doses of ATRA. Treg cells converted by ATRA/TGF-1 had high expression of mucosal tissue homing receptors and localized to the small intestinal lamina propria after injection into mice. The authors demonstrate that ATRA induces Treg cells with gut-homing receptors in human and mouse T cells.

Tumors Escape Immune Destruction

Long-term survival in cutaneous T cell lymphoma (CTCL) correlates with a high number of CTLs in lymphoma skin infiltrates. On p. 4272 , Winter et al. found that only one chemokine receptor, CXCR3, is down-regulated on circulating CD4⁺ and CD8⁺ T cells of CTCL patients compared with healthy controls. CXCR3 also was expressed at very low levels on the circulating CTCL lymphoma cells. The number or cytotoxic potential of the circulating effector CD8⁺ T cells in CTCL patients was not different from that of controls. Normal levels of mRNA for the migration-competent form of CXCR3 were measured in purified CTCL CTLs by quantitative RT-PCR. Although the total cellular level of CXCR3 protein in CTCL CTLs was equivalent to that in healthy CTLs, it was relocated from the cell surface to endosomal compartments. The CXCR3 ligands CXCL10 and CXCL9 were increased in the sera of CTCL patients. Surface expression of CXCR3 on CTCL cells increased to con trol levels after incubation in serum-free medium. Freshly isolated CTCL CD4⁺ and CD8⁺ T cells failed to migrate in response to CXCR3 ligands in Transwell assays, whereas cells incubated in serum-free medium did migrate. There was a significant decrease in effector CD8⁺ T cells in CTCL skin lesions compared with blood, although the few cells detected by flow cytometry expressed CXCR3. CXCR3 ligand expression was detected in CTCL skin lesions by immunofluorescence. The authors demonstrate that down-modulation of CXCR3 on effector CTLs by CXCR3 ligands, possibly produced by CTCL cells, enables the tumor to escape immune destruction.

A Y Link to NKT Cell Development

Development of V14 invariant NK T cells (V14i NKT) occurs in the thymus and requires glycolipid selection. Although IFN-/ was suspected to play a role in development of this T cell subset, Wesley et al. (p. 3480 ) found that only male, but not female, IFN-/R^–/– C57BL/6 mice lacked V14i NKT cells in their spleens and livers. However, the IFN-/R^–/– cells from either sex expressed CD1d1 and presented lipid to V14i NKT cell hybridomas at levels comparable to those of wild-type cells. In contrast, IFN-/R^–/– males had increased numbers of NK1.1⁺CD1d1 tetramer^– and thymocytes compared with IFN-/R^–/– females, but the males had no change in thymic CD1d1 expression compared with wild-type controls. Male IFN-/R^–/– mice had fewer CD4⁺CD8⁺ and more CD4^–CD8^– T cells in their thymi than female mice. This distorted ratio also was seen in IFN-/R^–/–-derived thymocytes of irradiated wild-type male mice given a mixture of wild-type and mutant male bone marrow. IFN-/R^–/– thymocytes proliferated and survived equally in irradiated male and female hosts. The V14i NKT defect was not detected in IFN-/R^–/– on a 129 background or in C57BL/6 mice lacking either of two IFN-/ signaling components. IFN-/R ^–/+ mice derived from backcrosses of IFN-/R^–/– males with C57BL/6 or 129 wild-type females lacked V14i NKT cells, but mice from the converse backcrosses did not. The authors provide evidence for a unique Y-linked factor independent of IFN-/ in the development of V14i NKT cells in mice.

Ag-Independent TCES

The decline in the immune response to infection and vaccination in older individuals is coincident with CD8⁺ T cell clonal expansions (TCEs). Some TCEs develop in the absence of chronic infection, but their origins are poorly understood. In mice infected with Sendai virus, Ely et al. (p. 3535 ) found low frequencies of virus-specific memory CD8⁺ T cells in mice at 6 mo postinfection (p.i.) but high frequencies at 19–20 mo p.i. In general, central memory T cells increased and effector memory T cells decreased over time, but some older mice had high levels of effector memory T cells. The range of TCR V8 usage in T cells that were negative or positive for virus-specific tetramers increased between 1 and 3 mo and 19–20 mo p.i. Most of these potential TCEs were effector memory cells. Epitope-specific T cells, which constituted nearly 90% of the memory T cells from one mouse, were predominantly V3⁺ by spectratype and sequence analysis but did not express CD35 or CD69 activation markers. Sendai virus-specific TCEs from mice produced IFN- and TNF- ex vivo in response to peptide and proliferated in vitro in response to IL-15 and IL-2 in the absence of peptide. Epitope-specific TCEs survived at least 24 days in naive syngeneic mice after adoptive transfer. Central memory TCEs with restricted V usage also were detected in mice 20 mo p.i. with influenza virus. The data show that effector-competent TCEs develop at high frequency from virus-specific memory cells in mice long after recovery from Sendai or influenza virus infection. The authors suggest that the dominance of these TCEs reduces the overall size and diversity of the T cell pool in the aging animals.

Protecting Against Chlamydial Disease

Infertility can result from untreated Chlamydia trachomatis infections. A clearer understanding of the immunopathogenesis of chlamydial disease might lead to an effective vaccine. On p. 4027 , O’Connell et al. infected McCoy cells in culture with either wild-type or one of two plasmid-cured strains of a virulent C. muridarum strain. All three strains produced equivalent amounts of infectious progeny and induced infections with equivalent intensity and duration in mice. However, only the wild-type strain induced measurable inflammatory pathology in genital tract tissues from infected mice. Significantly reduced levels of TNF-, MIP-2, and several other cytokines were measured in genital tract secretions of mice infected with the plasmid-deficient strains. IL-8 secretion occurred only in TLR2-transfected human kidney cells infected with wild-type but not with either of the two plasmid-cured strains even though infection levels were the same for the three strains. Anti-C. muridarum IgG_2a serum titers and iliac node CD4⁺ T cell responses were similar for mice infected with either of the three strains. Only mice infected with either plasmid-cured strain were protected from genital tract histopathology and scarring when challenged with virulent wild-type C. muridarum 98 days postinfection. The data suggest that C. muridarum pathology results from a TLR2-dependent response regulated by the bacterial plasmid. The authors propose that plasmid-cured strains of chlamydia could be used as vaccines to prevent the human disease.

Costimulation Is Not Always Good

Current vaccine strategies in cancer therapy involve enhanced costimulation of naive CD8⁺ T cells by immunization with APCs expressing several costimulatory molecules. However, the effect of costimulation on effector/memory CD8⁺ T cells is not known. Mostböck et al. (p. 3524 ) used an immunodominant influenza virus epitope or its altered peptide ligands (APLs) in in vitro reactions with CFSE-labeled effector/memory epitope-specific TCR transgenic CD8⁺ T cells. They found no proliferation to intermediate or weak APLs in the presence of APCs expressing only H-2D^b and B7.1 (APC^low). Effector/memory CD8⁺ T cells lysed target cells only in the presence of the immunodominant epitope or a strong APL. Effector/memory CD8⁺ T cells generated in vitro or in vivo by various APLs had similar proliferative and cytokine responses when exposed to the immunodominant epitope, but only the cells generated by the immunodominant epitope or strong APL killed the target cells and expressed granzyme B. In vitro, effector/memory CD8⁺ T cells had lower TNF- and IFN- production and reduced proliferative responses to intermediate and weak APLs when cultured with APC^high (APCs expressing ICAM-1, B7.2, and LFA-3) vs APC^low; blocking of ICAM-1 on APC^high increased the proliferative and cytokine responses. Effector/memory CD8⁺ T cells generated in vitro to the immunodominant epitope by APC^high had reduced cytotoxicity for target cells presenting the immunodominant epitope, lower levels of granzyme B, and less phosphorylated ERK1/2 compared with cells generated by APC^low. Mice vaccinated with APC^high generated CD8⁺ T cells with lower cytotoxicity than those from mice vaccinated with APC^low, but levels of CD8⁺ T cell proliferation were comparable. The data suggest that mice repeatedly vaccinated in the presence of high levels of costimulation develop reduced cytotoxicity, especially against weak APLs.

Milking MS and EAE

Disease progression is well described for multiple sclerosis (MS) and its mouse model experimental autoimmune encephalomyelitis (EAE). However, not much is known about molecular mechanisms in the disease process. Otaegui et al. (p. 4074 ) made a longitudinal analysis of transcription in lymph nodes and spinal cords of NOD mice at various times up to 18 days after immunization with a myelin oligodendrocyte glycoprotein peptide. Animals with a similar disease course were analyzed as a group. The number of genes in lymph nodes differentially expressed compared with controls decreased with time, whereas the number in spinal cords increased. Focusing on lymph node profiles, the authors found 279 genes differentially expressed in animals at peak EAE vs controls; six or fewer were detected at other stages of disease. Many of the 279 gene transcripts were reflective of an innate immune response. Of the six differentially expressed genes at the late recovery phase, four belonged to the casein family, one was a milk component, and the sixth was an inducer of mammary involution. Real-time PCR and immunohistochemistry of lymph nodes confirmed the results. Elevated expression of one of the casein genes was detected by quantitative RT-PCR in whole blood cells in 10 of 112 samples from MS patients; six of the 10 patients had recently suffered a clinical relapse. The authors propose that immune cells differentially expressing genes infiltrate spinal cords from lymph nodes during EAE progression. Most genes with differential expression were detected at the peak of the disease, although six genes related to milk production or mammary gland development were detected at the late recovery stage in EAE and MS.

Summaries written by Dorothy L. Buchhagen, Ph.D.

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