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Dual nectin receptors on NK cells
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H2M and MHC class II repertoire
The class II-associated peptide (CLIP) derived from the type II membrane glycoprotein, invariant chain (Ii), interacts with the peptide-binding groove of the MHC class II molecule to regulate MHC peptide loading. However, it is not clear how the affinity of CLIP for MHC class II affects the peptide repertoire. Honey et al. (p. 4142 ) developed strains of transgenic mice in which the mouse Ii was replaced by a wild-type human Ii (hIiWT) gene or by an hIi gene with mutations in the CLIP region that decreased its affinity for I-Ab (hIiBAD-CLIP). Cell surface expression of I-Ab and MHC class II was comparable in both transgenic strains. CLIP degradation products were more diverse in the hIiBAD-CLIP mice and readily dissociated from MHC class II molecules. Expression of MHC class II in H-2M-/- mice was rescued fully by crossing in hIiWT but only partially by crossing in hIiBAD-CLIP. Both MHC class II peptide loading equal to that of wild-type mice and efficient Ag presentation to T cells were seen with splenocytes from hIiWT and hIiBAD-CLIP animals. But, the additional lack of H-2M in the two strains greatly increased the peptide loading and diversity of the repertoire and elicited a greater T cell response in those animals carrying hIiBAD-CLIP vs hIiWT. Expression of hIiBAD-CLIP restored CD4+ T cell levels in Ii-/-H-2M-/- mice to 60% of those of wild-type mice, whereas hIiWT had no affect on CD4+ T cell levels. The authors propose that H-2M acts as a chaperone to stabilize the peptide:MHC class II complexes in the face of lowered CLIP affinity.
Rethinking glomerulonephritis
Linear binding of IgG to the glomerular basement membrane (GBM) is the hallmark of Goodpasture’s syndrome. However, the precise mechanism by which autoantibodies are induced in glomerulonephritis (GN) has not been determined. Wu et al. (p. 4567
) expanded studies on their rat model of GN in which transfer of T cells specific for the Goodpasture’s Ag on collagen IV, Col4
3NC1, or injection of a T cell epitope, pCol (28–40), derived from the Ag could induce anti-GBM GN. GBM-bound IgG was detectable by immunofluorescence 5 days after glomerular injury in 76% of peptide-injected rats. Eluted GBM-bound IgG, but not circulating anti-pCol (28–40), immunostained native GBM in kidney sections; anti pCol (28–40) Ab, but not eluted GBM Ab, reacted with the peptide. A pCol (28–40) peptide with a substitution at aa 33 (p33A), within the T cell epitope, was unable to induce GN in injected rats. In contrast, a pCol (28–40) peptide with a substitution at aa 40 (p40A), that mutated a B cell epitope nested within the T cell epitope, and a derived 11-mer, pCol (29–39), did induce GN. Binding of IgG to GBM was detected in 65% of rats immunized with p40A but in no animals immunized with p33A. The immunofluorescent staining pattern of eluted anti-GBM Abs on GBM was broader than a control Col44-specific mAb; the eluted Ab immunoprecipitated only native GBM proteins. The authors conclude that a single T cell epitope of Goodpasture’s Ag can initiate severe GN and leads to the subsequent production of anti-GBM Ab.
A novel IFN-
-induced protein
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stimulates expression of a wide variety of genes in response to viral infection or inflammation. One of those genes is uteroglobin, the founding member of the newly formed secretoglobin (SCGB) superfamily of proteins. A new member of this family of proteins characterized by anti-inflammatory, anti-chemotactic tumor suppressor-like activities is described by Choi et al. (p. 4245
). RT-PCR amplification of total RNA from a human lymphoblast cell line using primers for one member of the SCGB family, lipophilin-B, yielded a DNA sequence that was unrelated to lipophilin-B. The open reading frame of 252 nucleotides encoded a protein of 83 aa and was derived from a 3-kb gene on human chromosome 11. High level expression of the mRNA was detected in ovary, lymph node, tonsil, and a lymphoblast cell line. As the expression of this mRNA was induced in lymphoblast cells by IFN-, but not by other cytokines, the authors named it IIS (IFN--inducible secretoglobin). IIS mRNA expression was stimulated in activated CD8+ T cells and CD19+ B cells compared with resting cells. Chemotactic migration and invasion of lymphoblast cells transfected with IIS antisense oligonucleotides were inhibited compared with untreated or IIS sense oligonuleotide-transfected cells. The authors speculate that this newest member of the SCGB superfamily may mediate IFN--induced immunological functions. Asthma and exercise
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13- and 3-fold, respectively, in bronchoalveolar lavage fluid from the lungs of sensitized, exercised animals vs sensitized, sedentary mice. Exercise decreased OVA-specific, but not total, IgE levels in sensitized animals, and decreased the phosphorylation of I
B and translocation of the NF-B subunit p65 in lung cells seen in sedentary mice. The authors conclude that moderate intensity aerobic exercise reduces asthmatic inflammation of the lung by modulating NF-B activation. IL-12-inducible genes
Although IL-12 is being used clinically to treat human cancers, the cellular and molecular mechanisms of the antitumor and antimetastatic activities of the cytokine are not fully understood. For example, many IL-12 effects are mediated through IFN-, yet IL-12 antitumor activity is seen in IFN--deficient mice. Shi et al. (p. 4111
) studied the genome-wide effects of IL-12 on growth and metastasis of a mouse mammary tumor cell line, 4T1, in syngeneic wild-type and IFN--/- BALB/c mice. IL-12 was injected into the animals every 2 days beginning 7 days after s.c. injection of 4T1 cells. The IL-12-treated mice had tumor growth reduction (36% in wild-type and 31% in IFN--/- mice) compared with untreated controls; both also had fewer lung metastases, with a greater effect seen in the treated wild-type animals. IL-12 blocked the formation of blood vessels and increased the number of tumor-infiltrating lymphocytes. Lung metastases were reduced in animals whose primary tumors were removed on days 14 and 21 and then given IL-12 compared with untreated animals. Tumor growth and metastases in naive mice were identical for tumors from untreated or IL-12-treated mice. Global gene expression analyses were performed on RNA samples from four groups of tumors on day 28: wild type and IFN--/-, each treated with either PBS or IL-12. Four distinct gene clusters were identified: 67 IFN--independent and 50 IFN--dependent genes had enhanced expression with IL-12, and 65 IFN--dependent and 2 IFN--independent genes had reduced expression with IL-12.
Collateral priming of T cells
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Summaries written by Dorothy L. Buchhagen, Ph.D.
Related articles in The JI:
-Independent Mechanisms
Stimulates the Expression of a Novel Secretoglobin That Regulates Chemotactic Cell Migration and Invasion
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