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IN THIS ISSUE

Cystatin C not needed

The cysteine protease inhibitor cystatin C (CyC) has been thought to sequester MHC class II (MHC II) in endosomal compartments in immature dendritic cells (DC). Mature DC then presumably gain the capacity to present Ags by down regulating CyC expression. El-Sukkari et al. (p. 5003 ) tested this model. They found that CyC was differentially expressed among splenic DC populations. CyC levels were highest in CD8⁺ DC compared with CD4⁺ DC and CD4^-CD8^- DC, and these differences were maintained even after maturation of each population. CyC localized in MHC II⁺ lysosomal-associated membrane protein⁺ compartments in both immature and mature CD8⁺ DC. Invariant chain (Ii) processing and MHC II peptide loading were comparable in CD4⁺ and CD8⁺ DC. Maturation of MHC II was inhibited to the same extent in CD4⁺ and CD8⁺ DC from mice deficient for cathepsin S, the enzyme that cleaves the degradation product of Ii from MHC II. Distribution of MHC II in immature and mature DC from CyC-deficient mice was identical, and CyC-deficient CD8⁺ DC were efficient at presenting exogenous Ags to T cells. MHC II molecules in DC from CyC^-/- and wild-type mice accumulated in lysosomal-associated membrane protein⁺ compartments and redistributed to the cell surface after maturation. CyC deficiency did not have a deleterious effect on Ii degradation or MHC II-peptide complex formation. The experiments demonstrate that CyC is neither necessary nor sufficient to control MHC II Ag presentation in DC. Rather, they suggest that control is based on regulating the rate of endocytosis of the MHC II-peptide complexes.

Treating type 1 diabetes

One approach to treating type 1 diabetes is to tolerize autoreactive T cells without disrupting the ability of the immune system to fight microbial pathogens. Peptide-MHC II multimers have been effective in delaying the onset of autoimmune disorders. Masteller et al. (p. 5587 ) generated dimers of I-A^g7 covalently linked to the BDC2.5 mimotope-peptide 1040-31 (p31-I-A^g7) that reacted with BDC2.5 TCR transgenic CD4⁺ T (BDC2.5 Tg⁺ T) cells derived from a clone isolated from a diabetic nonobese diabetic (NOD) mouse. p31-I-A^g7 dimers specifically activated BDC2.5 Tg⁺ T cells in vitro, but they did not recognize or activate control NOD CD4⁺ T cells. Control I-A^g7 dimers recognized and activated control CD4⁺ T cells but not the BDC2.5 Tg⁺ T cells. TCR-deficient NOD mice adoptively transferred with in vitro-activated BDC2.5 Tg⁺ T cells developed diabetes within 6–10 days, whereas mice that received injections of p31-I-A^g7 dimers for 3 days after cell transfer did not develop diabetes until 21 days. Neither control dimers nor soluble peptide 1040-31 protected against diabetes. After p31-I-A^g7 dimer treatment, transferred BDC2.5 Tg⁺ T cells had an increased activation phenotype and increased cell death compared with controls. Surviving cells had reduced proliferative responses to peptide 1040-31 in vitro. Spleen cells from p31-I-A^g7 dimer-treated animals produced higher levels of IL-10 and lower levels of IFN- than control animals. Injection of anti-IL10R mAb into mice receiving activated BDC2.5 Tg⁺ T cells and p31-I-A^g7 dimers abrogated the protection against diabetes. The results show that peptide-I-A^g7 dimers induce tolerance through induction of clonal anergy and anti-inflammatory cytokines.

Tapasin is not a peptide editor

Tapasin is a component of the peptide loading complex that binds peptides to MHC class I molecules in the endoplasmic reticulum. It has been thought to function as a peptide editor by selecting high-affinity peptides. Zarling et al. (p. 5287 ) compared HLA-B8 expression on cells lacking tapasin with that on tapasin-deficient cells that had been transfected with vectors expressing either full-length tapasin or soluble tapasin that did not associate with TAP, the transporter associated with Ag processing. Steady-state levels of HLA-B8 molecules expressed at the cell surface were comparable in the two tapasin transfected cell lines, and levels in both lines were four times higher than the level in tapasin-deficient cells. A small fraction of HLA-B8 molecules was resistant to treatment with acid and with the inhibitor brefeldin A in cells expressing full-length tapasin and, to a lesser extent, in cells expressing soluble tapasin, indicating that tapasin acted intracellularly to stabilize a more receptive peptide binding conformation. HLA-B8-associated peptide profiles from cells expressing either form of tapasin were found by mass spectrometry to be similar to each other but distinct from the peptide profile in tapasin-deficient cells. Moreover, the peptides from cells lacking tapasin had higher average binding affinities than peptides from cells expressing either form of tapasin. The results suggest that tapasin facilitates peptide binding by broadening the peptide repertoire and by stabilizing MHC-peptide complexes rather than by editing peptides.

NIMA-induced allo-tolerance

Allograft tolerance occurs during pregnancy. Yet neither the mechanism nor the route for acquired tolerance to noninherited maternal Ags (NIMA) is understood. Andrassy et al. (p. 5554 ) crossed H-2^b/d F₁ females with H-2^b/b males to generate H-2^b/b offspring exposed to NIMA-H-2^d. Fifty-seven percent of H-2^d/d heart grafts transplanted into the NIMA-H-2^d-exposed animals were retained for more than 180 days. All controls (H-2^k/k hearts into NIMA-H-2^d-exposed recipients, H-2^d/d hearts into H-2^b/b recipients not exposed to H-2^d) were rejected within 9 days. Acceptance of transplants also required nursing by H-2^b/d females. H-2^d-specific cells were detected by PCR only in offspring exposed both in utero and orally to NIMA-H-2^d. Histopathology of rejected H-2^d/d hearts in NIMA-H-2^d-exposed mice was less severe than in controls. The frequency of T cells producing IL-5, IFN-, and IL-2 from NIMA-H-2^b/b mice responding to H-2^b/d splenocytes was greatly reduced vs controls. Injection of an immuno-dominant H-2L^d peptide into pregnant H-2L^d-negative mice rendered recipient spleen cells nonresponsive to peptide challenge in vitro. Tolerant NIMA-H-2^d-exposed mice had lower levels of IgG1 and IgG2a Abs after H-2^d heart transplants compared with controls. The authors conclude that the NIMA effect involves suppression of allospecific T and B cell responses in the offspring.

Myeloid C3

Humoral response to HSV is dependent on the classical complement pathway. Whereas liver is the primary source of complement, there is some evidence that nonhepatic sources of complement are important in immune function. Verschoor et al. (p. 5363 ) reconstituted lethally irradiated wild-type or C3^-/- mice with bone marrow (BM) cells from wild-type or C3^-/- mice. The inability of irradiated C3^-/- mice to develop serum anti-HSV Abs after intradermal HSV infection was corrected by injection with wild-type BM, whereas injection of C3^-/- BM into irradiated wild-type or C3^-/- mice was ineffective. Injection of wild-type BM into irradiated wild-type mice was completely effective. The frequency of HSV-specific B cells and germinal centers was reduced only in draining lymph nodes from the two groups of mice reconstituted with C3^-/- BM. There was no impairment in CD4⁺ T cell response to HSV Ag in any of the groups of animals. All groups of animals except C3^-/- mice receiving C3^-/- BM developed Ab against a non-HSV Ag injected i.v. Infiltration of mononuclear cells into the HSV-infected dermis was detected in all groups of mice. C3 message was seen in CD11b^high/CD11c^neg granulocytes and monocytes isolated from lymph nodes of animals injected with wild-type BM but not in mice receiving C3^-/- BM. The results indicate a role for myeloid cell-derived C3 in the Ab response to HSV dermal infection.

EBV-induced class switch recombination

Immunoglobulin heavy chain class switching in B cells can be induced by viral and bacterial proteins that up-regulate CD40 ligand on CD4⁺ T cells. Such switching can lead to autoimmune and atopic disorders. He et al. (p. 5215 ) studied EBV-induced class switch recombination (CSR). Noninfected IgD⁺ B cells from healthy subjects lacked the extrachromosomal switch circles (SC), chimeric I-Cµ circle transcripts (CT), noncoding germline I_H-C_H transcripts and transcripts for the enzyme that induces CSR, all of which were found in lymphoblastoid and EBV⁺ B cells. Infection of the noninfected IgD⁺ B cells with EBV led to appearance of SC and the transcript for the CSR enzyme. EBV^- Burkitt’s lymphoma (BL) cells transfected with expression vectors for two EBV proteins, latent membrane protein 1 (LMP1) and, to a lesser extent, LMP2A, contained CT and mature CSR transcripts, whereas EBV^- BL cells transfected with empty vectors or expression vectors for other EBV proteins did not. In addition, LMP1 and LMP2A up-regulated expression of B cell activating factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL), two inducers of T cell-independent CSR in the same B cells. Transfection of LMP-transfected EBV^- BL cells with increasing amounts of IB inhibited activation of BAFF, indicating that NF-B is crucial for the up-regulation of BAFF by LMP1. Purified EBV-infected IgD⁺ B cells also expressed BAFF and APRIL along with LMP1-induced surface proteins. Exposure to decoy receptors specific to EBV-induced surface proteins reduced SC, CT and CSR enzyme transcripts in lymphoblastoid cells. The findings suggest that EBV could play an important role in the pathogenesis of disorders associated with aberrant IgG, IgA, and/or IgE production.

T cells can help B cells

Interactions between B and T cells in germinal centers (GC) are critical for Ig somatic hypermutation (SHM), affinity maturation and memory development. However, it is not known whether T cells can participate in GC formation and Ig SHM. Zheng et al. (p. 4979 ) immunized TCR -deficient mice with a T-dependent Ag (4-hydroxy-3-nitrophenyl) acetyl conjugate of chicken globulin (NP-CGG). By 12 days, the number of splenic GC detected by immunohistology was approximately one-sixth of that seen in NP-CGG-injected wild-type mice. The GC in the mutant mice contained CD4⁺ T cells compared with CD4⁺ T cells in the wild-type mice. Frequencies of SHM in VDJ segments (V_H186.2 family) in isolated splenic GC B cells were comparable between TCR ^-/- and wild-type animals. Affinity-enhancing mutations in complementarity determining regions were positively selected and an affinity-reducing mutation was negatively selected in both strains of mice. A total of 55% of other V_H gene sequences from GC were mutated in TCR ^-/- mice compared with 0% in wild-type mice. Whereas the ₁ L-chain was found in NP-specific Abs in GC and sera in wild-type mice, the mutant mice used the L-chain. Moreover, IgM predominated in both primary and secondary responses in the TCR -deficient mice. The data show that T cells can provide help to B cells although the signals are different from those of T cells.

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

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