Most of us can remember a time when tonsils were taken out as a matter of course. Xu et al. (p. 276 ) have shown us another reason why one might want to keep them where they are. Extrafollicular B cells, such as those found in tonsillar mucosa, can mount a T cell-independent Ig response that is effective in controlling pathogens during the 5- to 7-day waiting period that T cell-dependent responses require. Using mucosal B cells from tonsils, the authors examined T cell-independent class-switch DNA recombination (CSR) from IgM to IgG and IgA in response to viral dsRNA. Tonsillar B cells expressed TLR3, the receptor for dsRNA. Xu et al. found that dsRNA did the following: 1) activated NF-κB through recruitment of the TLR3 adaptor protein TIR domain-containing protein inducing IFN-β (TRIF); 2) effected germline transcription of downstream CH genes; and 3) induced expression of the activation-induced cytidine deaminase (AID). Mucosal TLR3-expressing dendritic cells released the B cell-activating factor of the TNF family (BAFF) in response to dsRNA, which enhanced B cell production of IgG and IgA. Thus, the authors have described a new model for innate mucosal B cell responses to viral pathogens and have implicated resident dendritic cells in this T-independent defense.

During placental formation, the trophoblast must literally invade the maternal decidua, a feat of immunological balance that is still somewhat mysterious. An elegant immunogenetic study by Sharkey et al (p. 39 ) has shed light on how this occurs. Compared with those in the peripheral blood, uterine NK cells residing in the decidua expressed higher levels of both activating and inhibitory killer Ig-like receptors (KIR) specific for trophoblast-expressed HLA-C. In contrast, the expression of the KIR specific for HLA-B was similar in both decidual and peripheral blood NK cells. The authors report that HLA-C-specific KIR expression intensity was increased on uterine NK cells during the start of pregnancy and declined as gestation proceeded. These uterine NK cells also demonstrated better recognition of HLA-C tetramers compared with their peripheral blood counterparts. Crosslinking of HLA-C-specific KIR molecules resulted in cytokine secretion, suggesting functionality. Thus, uterine NK cells at the maternal-fetal interface may be able to modulate their KIR expression throughout pregnancy to recognize the HLA-C expressed by the trophoblast. Importantly, this is a novel demonstration of selective regulation of HLA-C KIR without the concomitant loss of another KIR.

Adaptive immune responses require lymphocytes to reprogram their genetic expression in order to differentiate. This differentiation includes changes to the assembly of Ag receptor genes by V(D)J recombination, a process dependent on epigenetic modifications to histones and DNA. Modification of histone H3 lysine 9 (H3K9) is an important component in the mammalian epigenome as this residue when acetylated is associated with active gene expression, but when it is methylated it is associated with gene silencing and a more closed chromatin structure. To test the importance of methylation of histone H3 at lysine 9 (H3K9me) during lymphocyte development, Thomas et al. (p. 485 ) used mice whose lymphocytes were deficient in histone methyltransferase G9a (G9a−/−), which is a critical H3K9 methyltransferase. This deficiency resulted in a loss of H3K9me2 in lymphocytes. The authors were surprised to find that lymphocyte development was normal in these mice with comparable numbers of splenic and bone marrow B cells, and of splenic T cells, as in wild-type mice. However, G9a-deficient B cells cross-linked with anti-IgM demonstrated a 4-fold reduction in proliferation compared with wild type. When G9a−/− mice were immunized with the T cell-dependent Ag KLH, the IgH isotypes produced were unchanged compared with the wild type, but usage of Igλ was reduced. The authors concluded that G9a methyltransferase controlled the usage of Igλ light chains and gene assembly in bone marrow precursors, indicating that the H3K9me2 epigenetic modification plays a very specific role in lymphocyte function.

What makes a self-specific T cell pathogenic is poorly understood. To shed light on this question, Alli et al. (p. 136 ) used a TCR retroviral transgenic (retrogenic) model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) to compare the pathogenic characteristics of different TCR. Five H-2 Ab/MOG35–55-specific TCR were tested in TCRαβ-deficient hybridoma cells or Rag1-deficient (Rag1−/−) bone marrow progenitor cells transferred into Rag1−/− mice (retrogenic mice). Different MOG-specific TCR in the transduced hybridoma cells had distinct proliferative responses to cognate Ag. T cells were detected within 4 wk in retrogenic mice, with variable levels of engraftment among individual mice. The phenotype of detected T cells was CD4+CD25 naive cells, and cellular responses mirrored the results found with the transduced hybridomas. While all MOG-specific TCR-expressing mice succumbed to EAE through immunization, some mice developed spontaneous disease. Surprisingly, this did not correlate with the functional affinity of the TCR but rather with the level of TCR engraftment in the individual mouse. The authors have not only developed an elegant system to compare T cell functionality in EAE but have also implicated the number of autoreactive T cells as a determinant of autoimmunity.

When the T cell receptor engages a specific peptide-MHC (pMHC) complex, the resultant conformational change in CD3ε exposes its proline-rich sequence (PRS). This recruits the cytoskeletal adaptor Nck and allows phosphorylation of the CD3ε ITAM. However, some Ag can respond to TCR ligation independently of the CD3ε PRS. Tailor et al. (p. 243 ) have now established that this interaction is necessary for low-avidity peptide ligands but can be overridden with peptides of higher avidity. The authors demonstrated that the CD3ε PRS was necessary for the pMHC:TCR-induced phosphorylation of CD3ε and for subsequent recruitment of PKCθ into the immunological synapse. Thus, a series of hierarchal steps have been determined. While these two signaling events were unnecessary for CD8+ T cells to respond to strong peptide agonists, they were a requirement for CD8+ T cell responses to weak peptide agonists. Taken together, these data demonstrate that certain T cell clonotypes use the CD3ε PRS and subsequent phosphorylation events to overcome low-avidity interactions and mount a competent immune response.

Genetic polymorphisms in the GPI-linked cell surface glycoprotein CD24 have implicated it in susceptibility to autoimmune diseases such as multiple sclerosis (MS) and systemic lupus erythematosus. Carl et al. (p. 320 ) examined how CD24 contributes to autoimmunity by generating CD24-deficient (CD24−/−) mice that expressed the 2D2 TCR specific for myelin oligodendrocyte glycoprotein 35–55, which is expressed in the thymus. 2D2 mice develop experimental autoimmune encephalomyelitis (EAE), a common murine model for MS. Unexpectedly, the authors found that compared with 2D2+CD24+/+ animals, 2D2+CD24−/− mice had abrogated development of EAE, as well as atrophic thymi and absent CD4+CD8+ and CD4+CD8 populations. To rescue 2D2 autoreactive T cells from deletion, CD24 expression had to be restored on the thymic stroma, as expression on the thymocytes themselves was not sufficient. However, CD24 deficiency did not hamper the thymic cellularity or development of T cells specific for the foreign Ag OVA in OTII CD24−/− transgenic mice, indicating that CD24 controls negative thymic selection but not positive thymic selection. The authors conclude that CD24 regulates the survival of autoreactive T cells, in essence allowing them to escape the thymus, thus providing insight into how CD24 enhances autoimmune susceptibility.

Tetraspanins, such as CD81, CD82, or CD9, have been shown to costimulate T cells when engaged in vitro. Serra et al. (p. 174 ) have described for the first time the proliferation of naive T cells in response to tetraspanin and CD28 coligation on the T cell surface. These cells develop a strong Th2 effector phenotype with secretion of IL-4, IL-5, IL-13, and IL-10. The cells can also secrete IL-2 and TNF-α, but IFN-γ expression is low or conspicuously absent. The coligation of CD81 and CD28 causes up-regulation of IL-4 production, STAT-6 phosphorylation, and GATA-3 expression in the precursors of the Th2 effectors. In essence, these cells develop a Th2 phenotype without ever passing through the Th0 intermediate phase. Interestingly, the only currently identified ligand for CD81 is the hepatitis C virus (HCV) envelope protein E2, with HCV causing chronic infection in the majority of those individuals infected. As a vigorous IFN-γ response is necessary for clearance of the infection, the authors have proposed that CD81 ligation by HCV E2 is mediating an Ag-independent T cell activation causing liver inflammation and impaired type 1 responses.

The expression of MHC I and related molecules can be enhanced by treatment with IFN-γ, including HLA-A, HLA-B, HLA-C, HLA-G, HLA-E, and CD1d. Liu et al. (p. 449 ) have found that IFN-γ down-regulates the neonatal Fc receptor (FcRn), which is the MHC I-related molecule that is responsible for maternal IgG transcytosis and acts in the gut to protect IgG and albumin from degradation. IFN-γ treatment of human intestinal epithelial lines, human PBMCs, and the THP-1 cell line caused a significant reduction in the RNA and protein levels of FcRn. Through the use of chromatin immunoprecipitation and gel mobility shift assays, STAT1 was found to bind to the IFN-γ activation site (GAS) in the promoter region of FcRn. JAK1 and STAT1 expression were found to be necessary to mediate the IFN-γ suppressive effect on FcRn expression. Immunoprecipitation data indicated that the mechanism of STAT1 action may involve sequestering the transcriptional coactivators CBP/p300. Additionally, IFN-γ treatment of polarized lung epithelial monolayers inhibited the FcRn-dependent transcytosis of IgG. The authors demonstrate that the JAK1/STAT1 pathway was necessary and sufficient to mediate the IFN-γ-induced suppression of FcRn expression. These results suggest that this pathway can both positively and negatively regulate immune system gene expression.

Summaries written by Kira R. Gantt, Ph.D.