Changes In Major Histocompatibility Complex Class Research Articles

NK cells: tuned by peptide?

Natural killer cells express multiple receptors for major histocompatibility complex (MHC) class I, including the killer cell immunoglobulin-like receptors (KIRs) and the C-type lectin-like CD94:NKG2 receptors. The KIR locus is extremely polymorphic, paralleling the diversity of its classical MHC class I ligands. Similarly, the conservation of the NKG2 family of receptors parallels the conservation of MHC-E, the ligand for CD94:NKG2A/C/E. Binding of both CD94:NKG2 heterodimers and KIR to their respective MHC class I ligand is peptide dependent, and despite the evolution of these receptors, they have retained the property of peptide selectivity. Such peptide selectivity affects these two systems in different ways. HLA-E binding non-inhibitory peptides augment inhibition at CD94:NKG2A, while HLA-C binding non-inhibitory peptides antagonize inhibition at KIR2DL2/3, implying that KIRs are specialized to respond positively to changes in peptide repertoire. Thus, while specific KIRs, such as KIR2DL3, are associated with beneficial outcomes from viral infections, viral peptides augment inhibition at CD94:NKGA. Conversely, NKG2A-positive NK cells sense MHC class I downregulation more efficiently than KIRs. Thus, these two receptor:ligand systems appear to have complementary functions in recognizing changes in MHC class I.

“Hard” and “soft” lesions underlying the HLA class I alterations in cancer cells: Implications for immunotherapy

The ability of cancer cells to escape from the natural or immunotherapy-induced antitumor immune response is often associated with alterations in the tumor cell surface expression of Major Histocompatibility Complex (MHC) Class I antigens. Considerable knowledge has been gained on the prevalence of various patterns of MHC Class I defects and the underlying molecular mechanisms in different types of cancer. In contrast, few data are available on the changes in MHC Class I expression happening during the course of cancer immunotherapy. We have recently proposed that the progression or regression of a tumor lesion in cancer patients undergoing immunotherapy could be predetermined by the molecular mechanism responsible for the MHC Class I alteration and not by the type of immunotherapy used, i.e., interleukin-2 (IL-2), Bacillus Calmette-Guèrin (BCG), interferon-alpha (IFN-alpha), peptides alone, dendritic cells loaded with peptides, protein-bound polysaccharide etc. If the molecular alteration responsible for the changes in MHC Class I expression is reversible by cytokines ("soft" lesion), the MHC Class I expression will be upregulated, the specific T cell-mediated response will increase and the lesion will regress. However, if the molecular defect is structural ("hard" lesion), the MHC Class I expression will remain low, the escape mechanism will prevail and the primary tumor or the metastatic lesion will progress. According to this idea, the nature of the preexisting MHC Class I lesion in the cancer cell has a crucial impact determining the final outcome of cancer immunotherapy. In this article, we discuss the importance of these two types of molecular mechanisms of MHC Class I-altered expression.

274. Brain gene expression changes in MHC Class II genes and Neuropilin 2 associated with the transition from acyclic to cyclic ovarian function in postpartum beef cows

The aim was to identify hypothalamic genes associated with transition from acyclic to cyclic ovarian function in postpartum cows. Ovarian status was recorded at slaughter for primiparous Brahman cows (Zebu, Bos indicus) at 27–34 days postpartum and hypothalamic tissue was obtained at the same time. Ovaries were classified as: Ov1 (n = 4), follicles 4–5 mm; Ov2 (n = 4), follicles equal or larger 10 mm without ovulation; Ov3 (n = 4), corpus haemorrhagicum or corpus luteum. Hypothalamic regions were: H1 (SC-POA, APVN, anterior hypothalamic nucleus, anterior portion of the arcuate nucleus, nearby areas of the diagonal band of Broca, and medial septum); H2 (basal hypothalamus-median eminence, ventromedial hypothalamus, posterior portion of the arcuate nucleus, and anterior part of the mammillary body). Gene expression was determined using the Agilent bovine 44k DNA microarray and differential expression (DE) was ascertained by mixed model analysis. Functional clustering of DE genes using DAVID (www.david.abcc.ncifcrf.gov) revealed an enrichment of genes linked with synaptic transmission in H1 and H3 comparing Ov1 and Ov3. Three members of the major histocompatibility complex (MHC) class II gene family (BOLA-DQA1, BOLA-DQA2 and BOLA-DQB) showed a higher expression level in Ov2 than Ov1 in H1 and H2. BOLA-DGA2 and BOLA-DQB were downregulated in Ov3 when comparing Ov2 and Ov3. MHC family members have been associated with plasticity in the brain1. Functional clusters of genes involved in cell-cell adhesion were differentially expressed when comparing Ov1 and Ov2 (H2), and Neutropilin-2 which promotes GnRH neuronal migration2 was upregulated in Ov1. The findings provide preliminary evidence that gene expression related to cellular plasticity within the basal hypothalamus-median eminence is associated with the transition from acyclic to cyclic ovarian function in the postpartum cow. (1) Håvik B et al. 2007 Neuroscience 148:925–36 (2) Cariboni A et al. 2007 TRENDS in Neurosciences 30:638–44

The natural killer cell receptor Ly-49A recognizes a peptide-induced conformational determinant on its major histocompatibility complex class I ligand.

Natural killer (NK) cells are inhibited from killing cellular targets by major histocompatibility complex (MHC) class I molecules. In the mouse, this can be mediated by the Ly-49A NK cell receptor that specifically binds the H-2Dd MHC class I molecule, then inhibits NK cell activity. Previous experiments have indicated that Ly-49A recognizes the alpha 1/alpha 2 domains of MHC class I and that no specific MHC-bound peptide appeared to be involved. We demonstrate here that alanine-substituted peptides, having only the minimal anchor motifs, stabilized H-2Dd expression and provided resistance to H-2Dd-transfected, transporter associated with processing (TAP)-deficient cells from lysis by Ly-49A+ NK cells. Peptide-induced resistance was blocked only by an mAb that binds a conformational determinant on H-2Dd. Moreover, stabilization of "empty" H-2Dd heavy chains by exogenous beta 2-microglobulin did not confer resistance. In contrast to data for MHC class I-restricted T cells that are specific for peptides displayed MHC molecules, these data indicate that NK cells are specific for a peptide-induced conformational determinant, independent of specific peptide. This fundamental distinction between NK cells and T cells further implies that NK cells are sensitive only to global changes in MHC class I conformation or expression, rather than to specific pathogen-encoded peptides. This is consistent with the "missing self" hypothesis, which postulates that NK cells survey tissues for normal expression of MHC class I.

Patterns of major histocompatibility complex class II expression by T cell subsets in different immunological compartments. 2. Altered expression and cell function following activation in vivo.

This study characterizes antigen-induced phenotypic and functional aspects of major histocompatibility complex (MHC) class II expression on recirculating T cells in efferent lymph. In vivo secondary, but not primary challenge is associated with both kinetic and phenotypic alterations in class II expression by T cells. All three major T cell subsets, CD4+, CD8+ and T19+ (gamma delta T cell receptor), show an approximate four fold increase in the level of MHC class II expression during secondary responses. No changes in B cell expression of class II were seen. Resting efferent lymph T cells are predominantly either class II- or DR+DQ- but this changes to DR+DQ+ after antigenic challenge. The antigen-presenting function of these class II+ T cells was investigated at daily intervals after in vivo antigenic challenge. T cells from non-activated lymph nodes could not induce proliferation of antigen-specific T cells with soluble antigen but were weakly stimulatory in allo-mixed lymphocyte reaction (MLR) at high (> 2:1) stimulator cell ratios. Activated T cells isolated during secondary in vivo responses, and expressing increased quantities of MHC class II, were positive stimulator cells in the MLR. In contrast these cells could not present soluble antigen or trypsin-digested antigen to the T cell lines. In the MLR assays, the relative stimulation by class II+ T cells correlates with the levels of class II expression. We conclude from these experiments that both quantitative and qualitative changes in MHC class II, induced on T cells under physiological conditions, play a role in the regulation of the immune response in vivo but that that role is not simply one of presentation of soluble antigen.