Disease relevance of H2-M3

• Impaired response to Listeria in H2-M3-deficient mice reveals a nonredundant role of MHC class Ib-specific T cells in host defense [1].
• H2-M3 major histocompatibility complex class Ib-restricted CD8 T cells induced by Salmonella enterica serovar Typhimurium infection recognize proteins released by Salmonella serovar Typhimurium [2].
• It also expands the range of pathogens that induce H2-M3-restricted CD8 T cells to include an example of gram-negative bacteria [2].
• H2-M3-restricted T cells in bacterial infection: rapid primary but diminished memory responses [3].
• In vitro stimulation of mouse splenocytes with hemagglutinin (HA) 173-190, a peptide derived from influenza virus hemagglutinin (A/JAP/305/57, H2N2), induces CTLs that are directed to the MHC class Ib molecule, H2-M3 [4].

High impact information on H2-M3

• H2-M3, a full-service class Ib histocompatibility antigen [5].
• H-2M3 presents a Listeria monocytogenes peptide to cytotoxic T lymphocytes [6].
• M3 is as divergent from classical, antigen-presenting H-2 molecules as from other class I genes of the Hmt and the Qa/Tla regions [7].
• Having defined H2-M3 as the positively selecting MHC molecule, the severely limited number of H2-M3 binding peptides allowed us to characterize an NADH dehydrogenase subunit 1 (ND1)-derived peptide as the physiological ligand of positive selection [8].
• Positive selection of an H2-M3 restricted T cell receptor [8].

Chemical compound and disease context of H2-M3

• H2-M3-restricted presentation of N-formyl methionine (f-Met) peptides to CD8(+) T cells provides a mechanism for selective recognition of bacterial infection [9].

Biological context of H2-M3

• The major histocompatibility complex (MHC) class Ib molecule H2-M3 primes the rapid expansion of CD8+ T cells by presenting N-formylated bacterial peptides [1].
• Although H2-M3-restricted CD8+ T cells constitute a significant proportion of the anti-listerial CD8+ T cell repertoire, the kinetics and magnitude of MHC class Ia-restricted T cell responses are not altered in H2-M3-deficient mice [1].
• It is possible that the Hmt gene product is the N-formyl peptide receptor itself and that it represents a class I antigen presentation molecule specialized for binding, transport, and immune presentation of N-formyl-peptide antigens of mitochondrial and prokaryotic origin [10].
• Backcrossing heteroplasmic mice with CAST/Ei, a strain in which the MHC class Ib molecule H2-M3 is silent, completely abolished selection against NZB mtDNA in the spleen [11].
• The COI mitochondrial gene encodes a minor histocompatibility antigen presented by H2-M3 [12].

Anatomical context of H2-M3

• Thus, the early H2-M3-restricted response temporally bridges the gap between innate and adaptive immune responses, subsequently affecting the function of both branches of the immune system [1].
• The mouse MHC class I-b molecule H2-M3 has unique specificity for N-formyl peptides, derived from bacteria (and mitochondria), and is thus a pathogen-associated molecular pattern recognition receptor (PRR) [13].
• Mta, the maternally transmitted antigen of mice, is a hydrophobic, N-formylated mitochondrial peptide, MTF, presented on the cell surface to cytotoxic T lymphocytes by a novel major histocompatibility complex class I molecule, encoded by H-2M3 [7].
• We propose that Hmt encodes a class I histocompatibility antigen that acts as a restricting element for the Mtf gene product, thus meeting the requirements of T killer cell recognition [14].
• This membrane orientation offers an explanation for the protection of the epitope from deformylases present in the bacterial cell and suggests an explanation for the ability of phagocytes to present H2-M3-restricted bacterial epitopes via a vacuolar TAP-independent mechanism [15].

Associations of H2-M3 with chemical compounds

• When formylated D-alanine or D-methionine replaced the native methionine, these peptide derivatives did not show significant binding to M3a [16].
• Additionally, the ability of M3a to discriminate between the optical forms of methionine and alanine demonstrates that this N-formyl pocket is stereospecific in its ability to bind peptide [16].
• Substitutions with other hydrophobic amino acids such as N-formyl phenylalanine and N-formyl valine had no significant effect on the ability of these Mtf alpha analogues to sensitize target cells (M3a, Mtf beta) to M3a, Mtf alpha-specific CTL [16].
• Listeria-encoded fMet peptide epitopes for H2-M3-restricted CTL have recently been identified [17].
• Cross-recognition of N-formylmethionine peptides is a general characteristic of H2-M3-restricted CD8+ T cells [18].

Regulatory relationships of H2-M3

• Tapasin enhances peptide-induced expression of H2-M3 molecules, but is not required for the retention of open conformers [19].

Other interactions of H2-M3

• We have recently established a TCR transgenic mouse model (C10.4 TCRtrans+) in which the transgenic TCR was selected on the nonclassical MHC class Ib molecule H2-M3 in conjunction with a physiologically occurring peptide derived from the mitochondrial NADH-dehydrogenase subunit 1 gene (9-mer peptide) [20].
• Thus, this report increases the number of MHC class Ib antigen-presenting molecules known for Salmonella antigens to three: Qa-1, HLA-E, and now H2-M3 [2].
• However, unlike the classical class I genes, the Thy19.4 gene maps approximately 1 cm distal to the Tla region of the MHC, in the same region as the gene encoding the Hmt element of the maternally transmitted antigen [21].
• These H2-M3-restricted T cells are cytolytic and produce interferon gamma [3].
• Incubation of RMA-S cells with oligomycin, an inhibitor of mitochondrial ATPase, strongly increased lysis by cytotoxic T lymphocytes (CTL) specific for the class Ib antigen H2-M3, and lysis by Qa-1b-specific CTL was restored [22].

References