B Cells Boost Tregs
Selection and differentiation of T cells, including most regulatory T cells (Tregs), occur in the thymus through cognate interactions between the TCR and peptide/MHC ligands on APCs. The Treg repertoire is shaped by medullary thymic epithelial cells (mTECs) and dendritic cells; however, the presence of intrathymic B cells and their expansion during autoimmune conditions presents the possibility that these cells may also play a role in Treg development. Using BAFF transgenic (BAFF-Tg) mice, in which B cell and Treg populations are both expanded, Walters et al. (p. 170) determined that the expansion of Tregs occurred in the thymus rather than the periphery in these mice. Histological analysis of thymi from wild-type (WT) and BAFF-Tg mice demonstrated that, although both of these strains had CD19+ B cells throughout the medulla, BAFF-Tg mice accumulated CD19+ B cells in clusters adjacent to both mTECs and Tregs. BAFF-Tg recipients transplanted with bone marrow (BM) from B cell–deficient μMT−/− mice demonstrated reduced numbers of thymic Tregs compared with BAFF-Tg mice transplanted with WT BM, suggesting that the presence of B cells is required for thymic Treg expansion. Compared with BAFF-Tg mice transplanted with μMT−/− BM and WT B cells, similarly reconstituted chimeras infused with MHC II−/− donor B cells, in which B cells fail to act as APCs for CD4+ T cells, including Tregs, demonstrated a reduction in thymic Treg numbers. These results suggested that the expansion of thymic Tregs is dependent on cognate B–T cell interactions. Additional experiments indicated that a diverse B cell repertoire was required to maximize thymic Treg expansion. Together, these results suggest that B cells may present Ags captured through the BCR on surface MHC class II molecules and thereby influence the development of thymic Tregs.
GAS M Protein Fuels IgA Nephropathy
IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis and is characterized by mesangial cell IL-6 inflammatory cytokine production and the deposition of matrix, IgA1, and C3 in the kidneys. IgAN onset is frequently preceded by Streptococcus pyogenes respiratory infection, and researchers have particularly studied IgA-binding group A Streptococcus (GAS) M proteins as potential triggers of IgAN. To determine the mechanism by which GAS M proteins influence IgAN pathogenesis, Schmitt et al. (p. 317) used surface plasmon resonance and ELISA techniques to study binding of the GAS M4 protein to galactosylated and galactose-deficient IgA1, which is found with greater frequency in renal deposits in IgAN patients. They found that M4 bound galactose-deficient IgA1 preferentially and that these two molecules enhanced mesangial cell proliferation and IL-6 and C3 production when added together to mesangial cell cultures. M4 was demonstrated by flow cytometry to bind human mesangial cells, and this binding was enhanced when mesangial cells were preincubated with galactose-deficient IgA1. Peptide and Ab blocking studies revealed that the M4 C-repeat conserved region was integral for mesangial cell binding. Together, these results suggest that binding of galactose-deficient IgA1 to GAS M proteins and deposition of these two molecules in the kidney may trigger deleterious IgAN pathogenesis by promoting inflammatory processes in mesangial cells.
Too Young To Remember Well
The high susceptibility and recurrence of infection in neonates suggests a potential impairment in protective immunity and the development of memory T cells. Whether this impairment is due to T cell–intrinsic defects or a poor priming environment remains to be elucidated. Using CD8+ T cells from gBT-I transgenic neonatal (6–7 d old) and adult (2–4 mo old) mice, which express a uniform peptide-specific TCR, Smith et al. (p. 177) demonstrated that although neonatal T cells proliferated more rapidly in response to peptide than adult T cells, this early proliferative response was not sustained. Transfer of neonatal or adult gBT-I transgenic T cells into adult WT recipients prior to systemic infection with Listeria monocytogenes showed that neonatal cells dominated the early response but failed to transition into long-lived memory cells. The subsequent recall response to infection was dominated by the adult gBT-I transgenic memory T cells. Phenotypic and gene expression analyses of neonatal and adult CD8+ T cells indicated that neonatal T cells expressed markers of terminal differentiation, whereas genes associated with memory T cell differentiation were predominantly expressed in adult cells. In similar experiments with a viral pathogen, neonatal CD8+ T cells also developed into terminally differentiated short-lived effector cells, demonstrating that the prior results were not pathogen-specific. Collectively, these results identify age-specific differences between adults and neonates in CD8+ T cell responses to infection that indicate an imbalance between effector versus memory T cell generation early in life.
AID Needs Aid
Somatic hypermutation (SHM) of Ig V region exons (V gene) and class switch recombination (CSR) of switch (S) region DNA are modulated by activation-induced cytidine deaminase (AID), which deaminates cytidines to uridines. Although both V genes and S regions are targets of AID, the exact mechanism by which AID is recruited to these target areas is unclear. Using chromatin immunoprecipitation (ChIP) experiments with CH12 B lymphoma cells, which undergo frequent CSR but not SHM, Matthews et al. (p. 252) demonstrated that AID preferentially bound to S regions, but not IgH (Igh) V genes. In CH12 cells, shRNA deletion of polypyrimidine tract binding protein-2 (Ptbp2), an RNA-binding protein that facilitates AID recruitment to S regions, led to a significant increase in AID binding to Igh V genes. Additional ChIP experiments demonstrated that AID targeted to V gene segments in Ptbp2-depleted CH12 cells was phosphorylated at serine 38, which is essential for AID-mediated SHM and CSR. However, SHM was not induced, suggesting that additional factors downstream of AID are essential for mediating SHM. This study demonstrates that S regions are preferred targets for AID, and in situations where AID is not sequestered to S regions, AID binding alone does not induce SHM, implicating additional factors in AID-mediated SHM.
WC1 Domains Alter Signal Strength
WC1 coreceptors, which share a high degree of similarity with CD163 receptors in humans, belong to the scavenger receptor cysteine rich (SRCR) family, and their expression on γδ T cells in cattle contributes to immune responses against bacteria. There are 13 WC1 genes in cattle that variably express two ectodomains and three endodomain sequences, but the expression pattern of these endodomains in γδ T cells and the differential contribution of their sequence variations to γδ T cell signaling are unknown. To determine the distribution of WC1 endodomain sequences in γδ T cells, Chen et al. (p. 379) performed gene-specific transcript analysis on γδ T cells that were divided into phenotypic subsets based on their ability to bind to three Abs specific for WC1 ectodomains: WC1.1+ (BAG25A-binding), WC1.2+ (CACTB32A-binding), and WC1.3+ (CACT21A-binding). They found that WC1.1+ cells contained type I, II, and III endodomain transcripts, WC1.2+ cells expressed type I and II endodomains, and WC1.3+ cells predominantly expressed type I endodomains. To determine if WC1 endodomain sequence variations in different γδ T cell subsets caused changes in intracellular signaling, the authors stimulated Jurkat cells bearing chimeric molecules composed of the human CD4 ectodomain fused to various WC1 endodomains. They found that cells expressing type III endodomains, which were phosphorylated at two tyrosines, exhibited more rapid and sustained tyrosine phosphorylation that resulted in greater IL-2 production compared with cells expressing type I or type II endodomains, which were phosphorylated only at one tyrosine. These results lend insight into how variations in WC1 endodomain expression can alter signal transduction during γδ T cell responses to bacterial infection.