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Progenitor epithelial cells

Regeneration and repair of airway epithelium after injury or in lung transplants is crucial to protect the host. Although circulating progenitor epithelial cells contribute to pulmonary recovery, their source is unknown. Gomperts et al. (p. 1916 ) found cells positive for cytokeratin 5 (CK5), a marker of early epithelial differentiation, and CXCR4 in mouse bone marrow and buffy coat. In males transplanted with syngeneic female tracheas, chromogenic and fluorescent in situ hybridization for the Y chromosome detected recipient epithelial cells in submucosal glands and ducts by day 3 posttransplant. Male cells also were detected in basal and apical epithelia at later times. Dual localization of CK5 and GFP was seen in tracheal sections from wild-type female tracheas transplanted into male GFP⁺ mice. Increased numbers of CK5⁺ cells in the circulation and bone marrow were measured in transplant recipients injected s.c. with one to three doses of CXCL12 compared with controls. CXCL12 mRNA and protein expression was higher in the lumen of submucosal glands and ducts in sex-mismatched tracheal transplants by day 3 posttransplant compared with control tracheas. CXCL12 protein expression was higher in basal cells by day 7 and in the apical surface of pseudostratified columnar epithelium by day 21. Tracheas in mice treated with neutralizing anti-CXCL12 Ab before transplant were phenotypically squamous metaplasia, and the cells stained positive for nuclear expression of p63, a marker of abnormal cell proliferation. No donor and few recipient epithelial cells were detected in mismatched transplants from CXCL12 Ab-treated mice, and the CK5⁺CXCR4⁺ cell population was diminished. The authors have identified and characterized a population of bone marrow and circulating CK5⁺ progenitor epithelial cells that localize to trachea transplants in mice.

Regulating inflammation

Although one or more MAPK phosphatase (MKP) has been implicated in limiting proinflammatory cytokine production during innate and adaptive immune responses, the mechanism involved is not known. Salojin et al. (p. 1899 ) generated MKP-1-deficient mice and found that low-dose LPS challenge increased their serum levels of six proinflammatory mediators 1.5- to 6-fold compared with wild-type littermates. All MKP-1^–/– mice died within 48 h of challenge, whereas all wild-type controls survived. Collagen-induced arthritis was accelerated and exacerbated in MKP-1^–/– mice compared with wild-type mice. Ex vivo treatment of bone marrow-derived macrophages with agents that activate different TLRs, including LPS and flagellin, induced higher levels of TNF- production, of CD86 and CD40 cell surface expression, and of p38 MAPK phosphorylation in MKP-1^–/– vs control cells. Pretreatment with a p38-MAPK inhibitor prevented the increased responses in the MKP-1^–/– cells. The experiments demonstrate that MKP-1 acts as a negative feedback regulator of p38-MAPK-regulated inflammatory responses to TLR signals in macrophages ex vivo and in a mouse model of autoimmune arthritis.

OX40 and transplant rejection

Memory T cells express alternative costimulatory molecules only after activation. However, the role of these molecules in memory T cell-mediated rejection of transplants is poorly understood. Vu et al. (p. 1394 ) demonstrated that naive C57BL/6 (B6) T cells transferred into B6. Rag-1-deficient hosts underwent homeostatic proliferation for 4 wk posttransfer, acquired a memory phenotype, and produced IFN- after in vitro stimulation with irradiated DBA/2 cells. Recipients rejected subsequent DBA/2 skin allografts within 14 days. CD28/CD154 blockade with CTLA-4Ig plus anti-CD154 Ab administered at the time of naive T cell transfer and skin grafting prevented rejection but had no effect in mice harboring homeostatic proliferation-generated memory T cells. Anti-OX40L mAb, but not anti-ICOS or anti-4-1BBL mAb, in combination with CD28/CD154 blockade but not alone prevented skin allograft rejection for more than 100 days in B6.Rag-1-deficient recipients with memory T cells. Anti-OX40L mAb plus CD28/CD154 blockade also prolonged skin allograft survival in B6 mice given T cells from B6 mice bearing DBA/2 skin allografts. Anti-OX40L mAb did not inhibit homeostatic proliferation or viability of transferred naive T cells but did impair IFN- production in recovered memory CD4⁺ T cells exposed to irradiated DBA/2 cells in vitro. The experiments show that OX40 is important in memory T cell-mediated rejection of skin allografts in mice insensitive to CD28/CD154 blockade.

"Cross-dressed" DCs

Optimization of immunotherapy involves activation of helper CD4⁺ T cells in addition to cytotoxic CD8⁺ T cells. Ostrand-Rosenberg and collaborators achieved this by coexpressing MHC class II (MHC II) and T cell costimulatory molecules in MHC class I (MHC I)⁺ tumor cells (MHC II vaccine). However, a contribution of dendritic cells (DCs) to MHC II vaccine efficacy has not been shown. In a new report from the Ostrand-Rosenberg laboratory on p. 1447, Dolan et al. injected a live sarcoma-specific MHC II vaccine into mice transgenic (Tg) for a diphtheria toxin receptor under control of a DC-specific promoter. Mice developed ascites tumors only when depleted of DCs by injection of diphtheria toxin before tumor challenge. Tg and non-Tg animals developed tumors when injected with live sarcoma cells. Splenic and bone marrow-derived DCs incubated with lysates of freeze-thawed, but not live, MHC II vaccine reacted with a mAb specific for the tumor MHC II molecule. Transfer of both MHC I and MHC II molecules to splenic DCs occurred for freeze-thawed MHC II vaccines derived from different tumor types and required cell-cell contact and expression of DC cell surface proteins. Confocal microscopy of DCs incubated with an MHC II vaccine lysate showed colocalization of tumor-derived lipid and MHC II molecules. Activation of CD4⁺ T cells carrying a tumor genotype-restricted Ag-specific TCR required DCs carrying MHC II-peptide complexes from genotypically identical tumor cells expressing the specific Ag. In vivo, CD4⁺ T cells from mice depleted of DC before challenge with Ag-specific MHC II vaccine were not activated in vitro by the Ag. The experiments demonstrate that "cross-dressed" DCs acquire MHC-peptide complexes from tumor cells and present them to T cells.

Thymocyte apoptosis

Glucocorticoids (GCs) are used clinically to induce apoptosis in leukemia and lymphoma. However, the pathway by which GCs act and their effect on different types of T lymphocytes are not fully understood. Wang et al. (p. 1695 ) determined that apoptosis induced by dexamethasone (Dex) treatment of thymocytes and splenic T cells required the GC receptor and was blocked by a GC receptor antagonist or cycloheximide. Treatment with a pan-caspase inhibitor, with an inhibitor of caspase-3, -8, -9, or B or with a proteasome inhibitor significantly reduced or eliminated Dex-induced apoptosis in thymocytes but had no effect on splenic T cells. Immunoblots showed processed caspase-3 only in treated thymocytes; no cleavage was seen in the presence of a caspase-3, -8, or -9 inhibitor. Confocal microscopy detected cathepsin B activation in thymocytes and localized it to lysosomes. No activation occurred in thymocytes treated with a cathepsin B or caspase-9 inhibitor. Cleavage within lysosomes and release of active cathepsin B to the cytosol were tracked by live imaging of single cells. T lymphoblastic leukemia cell lines, two of human origin and one of mouse origin, underwent apoptosis following Dex treatment; apoptosis was prevented by cotreatment of the cells with any of the caspase inhibitors. The data suggest that the execution phase of GC-induced apoptosis involves caspases, proteasomal degradation, and a lysosomal cathepsin B amplification loop in thymocytes and T lymphoblastic leukemia cells but not in splenic T cells.

Regulating diabetogenic T cells

Nonobese diabetic (NOD) mice develop spontaneous type 1 diabetes mellitus similar to the human disease. There is evidence that diabetogenic T cells are regulated by an unidentified subset of T cells. Cain et al. (p. 1645 ) saw accelerated insulitis and diabetes in TCR transgenic (Tg) NOD mice on a scid^–/– background (NOD.scid) compared with TCR Tg NOD controls. Cotransfer of splenocytes from prediabetic NOD mice abrogated diabetes induced by transfer of TCR Tg T cells into NOD.scid recipients. Cell fractionation and ablation studies identified a protective CD4⁺ NKT cell population absent in NOD mice deficient for the ₂-microglobulin gene. Diabetes was prevented by transfer of wild-type CD4⁺ NKT cells from 3 to 0 days before injection of the TCR Tg T cells. Injected GFP-TCR Tg or GFP-NOD splenocytes accumulated in pancreata of NOD.scid recipients; their cotransfer prevented the accumulation. CD1d-tetramer staining indicated large numbers of NKT cells in the pancreatic lymph node and pancreas of cotransferred recipients. Cotransfer of TCR Tg T cells and splenocytes from NOD mice deficient in IFN- resulted in diabetes, whereas cotransfer of splenocytes from NOD mice deficient in IFN-R--chain did not. However, transfer of TCR Tg T cells deficient in IFN-R--chain to wild-type NOD.scid recipients resulted in rapid diabetes. Cotransfer of wild-type splenocytes into wild-type or IFN-^–/– NOD.scid recipients restored regulatory control of diabetes. The authors conclude that an NKT cell subset producing IFN- indirectly inhibits activation of diabetogenic CD4⁺ T cells in the pancreas of a host responsive to IFN-.

Ig H chains in catfish

Somatic mutation of Ig H and L chains within the rearranged V(D)J segments in B cells results in higher affinity BCRs and Abs. Although somatic mutation has been studied extensively in mammals, there are few studies in bony fishes. Yang et al. (p. 1655 ) found a total of 79 nucleotide mismatches in J_H segments and 388 mismatches in V_H segments compared with germline segments in V_H family-specific cDNA clones from an Ig H chain-specific cDNA library constructed from an adult channel catfish spleen. G and C were preferentially mutated, whereas mutations in T were significantly lower than in A. V_H and J_H mutation hotspots were detected in AG and GC dinucleotides, a more restricted pattern than seen in human V_H analyses. V_H and J_H trinucleotide mutability indexes were low compared with humans. The G and C hotspots in catfish V_H fell into the AGCT and AGCA motifs, and the terminal position of AGCA was a significant target for A mutations. A highly mutable AGC codon contributed to a high CDR mutation rate. An analysis of three clonal sets of V(D)J rearrangements did not reveal selective forces to either conserve or accumulate mutations in CDR. This analysis of somatic mutation in the Ig H chain of the catfish identified mono-, di-, and trinucleotide targets within four-nucleotide motifs (AGCT and AGCA). The data indicate that the CDR-targeted somatic mutation emerged early in vertebrate evolution to diversify the H chain V region and increase the Ab repertoire.

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

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