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|Coordinate||71,373,728 bp (GRCm38)|
|Base Change||T ⇒ A (forward strand)|
|Gene Name||CD8 antigen, alpha chain|
|Synonym(s)||Ly-35, Lyt-2, Ly-B, Ly-2|
|Chromosomal Location||71,373,427-71,379,171 bp (+)|
|MGI Phenotype||Animals homozygous for a mutation in this gene lack CD8+CD4- cytotoxic T cells in the thymus and spleen and do not mount a cytotoxic response to alloantigens.|
|Amino Acid Change||Valine changed to Aspartic acid|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000068123] [ENSMUSP00000131873]|
AA Change: V59D
|Predicted Effect||probably damaging
PolyPhen 2 Score 0.989 (Sensitivity: 0.72; Specificity: 0.97)
AA Change: V59D
|Predicted Effect||probably damaging
PolyPhen 2 Score 0.961 (Sensitivity: 0.78; Specificity: 0.95)
|Phenotypic Category||CD4:CD8 - increased, CD4+ T cells - increased, CD4+ T cells in CD3+ T cells - increased, CD44 MFI in CD8 - increased, CD8+ T cells - decreased, central memory CD8 T cells in CD8 T cells - increased, effector memory CD8 T cells in CD8 T cells - increased, MCMV susceptibility, naive CD8 T cells in CD8 T cells - decreased, post-MCMV CD4+ T cells in CD3+ T cells - increased, post-MCMV CD8+ T cells - decreased, post-MCMV CD8+ T cells in CD3+ T cells - decreased|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Last Updated||2017-05-12 2:23 PM by Anne Murray|
|Record Created||2014-11-12 11:36 PM by Jin Huk Choi|
The alfalfa phenotype was identified among a subset of G3 mice of pedigree R1158 carrying ENU-induced mutations. The phenotype was characterized by effects mainly on CD8+ T cells: greatly reduced frequencies of CD8+ T cells (~10% of C57BL/6J; Figure 1), reduced frequencies of naïve CD8+ T cells among total CD8+ T cells (Figure 2), elevated frequencies of central (Figure 3) and effector memory CD8+ T cells (Figure 4), and elevated mean fluorescence intensity of CD44 immunostaining on CD8+ T cells (Figure 5), all in the peripheral blood. In addition, increased frequencies of CD4+ T cells were observed among total cells (Figure 6) or CD3+ T cells (Figure 7) in the peripheral blood (~150% of C57BL/6J); the CD4:CD8 cell ratio was consequently elevated (Figure 8). Five days after mouse cytomegalovirus (MCMV) infection, several mice displayed elevated MCMV titers in the spleen (Figure 9), suggesting increased susceptibility to the virus. With the exception of the CD4+ T cell phenotype, which was transmitted dominantly, all phenotypes were recessive with a detectable semidominant effect.
|Nature of Mutation|
Whole exome HiSeq sequencing identified 43 mutations in the G1 grandsire of the alfalfa pedigree. Each of the alfalfa phenotypes was mapped as a quantitative trait to a missense mutation of Cd8a: a T to A transversion at base pair 71,373,728 on chromosome 6 (GRCm38), corresponding to base pair 20,957 of the genomic DNA sequence (NC_000072.6). The mutation is positioned in exon 2 out of 6 exons (variant 1) or 5 exons (variant 2). Strongest linkage was found with the elevated CD4:CD8 T cell ratio using a recessive transmission model, with 5 affected mice homozygous for the mutation and 22 unaffected mice heterozygous (n = 10) or homozygous (n = 12) for the reference allele (P = 1.993 x 10-16; Figure 10).
The mutated nucleotide is indicated in red. The mutation results in a valine (V) to aspartic acid (D) substitution at position 59 (V59D) of both variants of the CD8 antigen, α chain (CD8α) and is predicted “probably damaging” by PolyPhen-2 (score = 0.989) (1).
The CD8α chain (also known as Lyt-2) is a 34-37 kDa single pass type I transmembrane glycoprotein of the immunoglobulin (Ig) superfamily. CD8α homodimerizes or heterodimerizes with CD8β (also known as Lyt-3) to form CD8αα or CD8αβ, respectively; CD8αα and CD8αβ display distinct expression patterns and functions. CD8αβ functions as a coreceptor for the T cell receptor (TCR) [reviewed in (2)]. In contrast, the function of CD8αα is unknown; it has been speculated to function as a TCR corepressor that negatively regulates cellular activation (3). Both CD8 isoforms bind to MHC class I molecules with equivalent affinity (4;5).
The 247-amino acid mouse CD8α chain consists of an N-terminal hydrophobic signal sequence (amino acids (aa) 1-27), an extracellular Ig-like domain (aa 28-139) followed by a hinge or stalk region containing three O-linked glycosylation sites (aa 140-196), a transmembrane segment (aa 197-217), and a cytoplasmic tail (aa 218-247) [Figure 11; reviewed in (6)]. The human and mouse CD8α protein sequences share 50% identity overall, with the greatest frequency of conserved residues in the transmembrane and cytoplasmic domains (79% and 55%, respectively). In mouse CD8α, cysteines 53 and 129 form an intramolecular disulfide bond that is characteristic of an Ig fold. Disulfide linkage with the CD8β protein is mediated by cysteines 178 and 193. The crystal structure of the Ig-like domains of mouse CD8αβ [Figure 12; PDB:2ATP] resembles the variable domain fragment (Fv) of an antibody, with each chain adopting a V-set type Ig fold (7;8); this structure is similar to that of the Ig-like domains in the CD8αα dimer (9;10). The two chains of both dimers have similar conformations, including a disulfide bond between the B and F β-strands, and a tryptophan on the C strand.
Either CD4 (see thoth) or CD8 and the TCR (αβ unless otherwise indicated) mediate T cell recognition of antigen-MHC complexes on the surface of antigen presenting cells. Expression of CD4 versus CD8αβ by a given T cell restricts TCR recognition of peptides to those bound to either MHCII or MHCI, respectively. CD4 and CD8αβ contact a conserved membrane-proximal region of their MHC target to enforce MHC class restriction [reviewed in (11)]. The molecular details of the interaction between CD8αα or CD8αβ with the peptide-MHCI complex (pMHCI) have been investigated by X-ray crystallography (8-10;12). The 3D structures revealed that the extracellular Ig-like domain of both CD8 dimers contact the α3 domain of the MHCI heavy chain, whereas CD8αα additionally contacts the α2 domain and β2-microglobulin (Figure 13; PDB:3DMM and Figure 14; PDB:1BQH), . Three complementarity-determining regions (CDRs), consisting of the BC loop (CDR1), the C’C” loop (CDR2), and the FG loop (CDR3), are involved in binding to the α3 domain of pMHCI, and in the case of CD8αα also to β2m. The CD8β subunit of CD8αβ is positioned next to the T cell membrane, while the CD8α subunit is distal from the T cell and close to the C-terminus of the MHCI α3 domain. Differences exist between the CD8αα/pMHCI interface and the CD8αβ/pMHCI interface despite the fact that overall conformations are quite similar. Importantly, nearly all MHCI residues making key contacts with CD8αα and CD8αβ are non-polymorphic; thus CD8αα and CD8αβ bind to different MHCI alleles with only subtly different affinities (4;13). However, reports suggest that CD8αβ is a more effective coreceptor than CD8αα in enhancing the range and sensitivity to peptide antigens and alloantigens recognized by TCRs (14-17). The stalk or intracellular region of CD8β may facilitate a configuration that promotes this augmented function (17-20).
Connecting the Ig-like domain to the transmembrane domain, the stalk region of CD8α contains numerous threonine, serine, and proline residues and is heavily O-glycosylated (21-23). CD8β is also O-glycosylated in its stalk region, and within the CD8αβ dimer; O-glycosylation of CD8β is developmentally regulated such that immature double positive thymocytes display lower levels than mature thymocytes (24-26). This relative difference influences thymocyte selection in that decreased levels of CD8β O-glycosylation in immature thymocytes correlate with increased affinity for pMHCI; the enhanced CD8-pMHCI binding promotes elimination of autoreactive T cells in the thymus (25;26). In contrast, higher levels of O-glycosylation in mature T cells reduce CD8 affinity for pMHCI, thereby requiring stronger TCR-pMHCI binding for T cell activation. The structural mechanism by which O-glycosylation alters CD8 affinity for pMHCI is unknown (27); in published 3D crystal structures the stalk region has been disordered. O-glycosylation has been reported to increase the rigidity of polypeptides, as observed in mucins, and may limit the mobility of the Ig-like domains of CD8αα and CD8αβ [reviewed in (2)]. O-glycosylation of CD8α does not appear to be developmentally regulated (24).
The cytoplasmic domain of CD8α binds to the Src family kinase Lck (see iconoclast) (28;29). Two cysteines in the CD8α cytoplasmic domain (C227 and C229 in mouse) are necessary for this interaction (30;31).
The alfalfa mutation lies within the extracellular Ig-like domain of CD8α, in the CDR1 which consists of the connecting loop between β-strand B and β-strand C.
CD8αβ is expressed primarily on TCRαβ+ thymocytes and peripheral cytotoxic T cells (32;33); the cell surface expression of CD8β requires association with CD8α (34;35). CD8αα is found on intestinal intraepithelial lymphocytes (36;37), TCRγδ+ T cells, and some natural killer (NK) cells and dendritic cells (DCs) (38). CD8αα is reportedly expressed on terminally differentiated human CD8+ T cells that have expanded during chronic viral infection (39).
T cells become activated when the TCR engages a peptide antigen in complex with an MHC molecule on the surface of a target or antigen-presenting cell. However, TCR-pMHC interaction is not by itself sufficient to induce an effective T cell response. Rather, engagement of pMHC by the TCR and either the CD4 or CD8 coreceptor is necessary for optimal T cell stimulation (40;41). For cytotoxic T cells, the interaction of CD8 with MCHI enhances the antigen sensitivity and response of the T cells to pMHC ligands (42). As discussed above, CD8 contacts invariant sites on the membrane-proximal region of the MHCI molecule in the context of the composite pMHCI complex. These sites are distinct and physically distant from the sites bound by the TCR, permitting both coreceptor and TCR to bind the same pMHCI complex (10). Absent CD8-pMHCI interaction, MHC class I-restricted immune responses including cytokine production and cytotoxic effector function are impaired (40;41). However, high-affinity pMHC/TCR interactions can in some cases compensate for a lack of CD8 engagement in terms of Lck activation, T cell proliferation, and cytotoxic T lymphocyte (CTL) activity (43). Discussed here is the TCR coreceptor function of the CD8αβ heterodimer; the function of CD8αα is unknown although it is suggested to act as a TCR corepressor (3).
The affinity of CD8αβ for pMHCI is 10- to 100-fold weaker than TCR-pMHC1 affinities [(5); reviewed in (2;44)]. During T cell activation, an ordered engagement in which TCR-pMHC interaction precedes CD8-pMHC binding dictates that contact between the TCR and pMHC prevails in T cell-antigen engagement (45;46). Rather than physically promoting initial TCR-pMHCI binding, the major function of CD8αβ is to recruit the kinase Lck to the TCR-MHC interaction site where it can phosphorylate immunoreceptor tyrosine-based activation motifs (ITAMs) on the cytoplasmic tails of associated CD3 proteins (see tumormouse, a mutation of Cd3e, and allia, a mutation of Cd247) (47;48). Their phosphorylation recruits and activates other proteins including ZAP-70 (ζ-chain-associated protein of 70 kDa; see murdock), SLP-76 (SH2 domain-containing leukocyte protein of 76 kDa), and LAT (linker for activation of T cells) necessary for signaling leading to T cell activation, proliferation, and differentiation (Figure 15; also see iconoclast for a description of TCR signaling). CD8α serves as a Lck docking site (28;29) through a ‘zinc clasp’ structure that tethers Lck to the CD8α cytoplasmic tail (49). A secondary function of the CD8-pMHCI interaction is to synergistically stabilize TCR-pMHCI interactions (46). However, it has also been reported that CD8αβ can play a critical role in promoting TCR-pMHCI binding, particularly for multimeric low-affinity pMHCI ligands (50;51).
TCR signaling is necessary for both adaptive immune responses and for thymocyte differentiation (Figure 16). Thymocytes are classified based on CD4 and CD8 expression, with the earliest thymocytes being CD4-CD8- (DN, double negative). DN thymocytes differentiate into CD4+CD8+ double positive (DP) cells, which undergo positive and negative selection following TCR-mediated interactions with self peptide-MHC complexes. During positive selection, DP cells with intermediate affinity for self-MHC mature into CD4+8- or CD4-8+ single positive (SP) cells, whereas strongly self-reactive DP cells undergo apoptosis during negative selection. CD8αβ is required for both positive and negative selection of DP cells in the thymus (52-54). Mice deficient in CD8α and/or CD8β displayed diminished or absent CD8+ T cells in the periphery, although thymocyte differentiation to the DP stage was intact. Consequently, cytotoxic responses against alloantigens and viral antigens were reduced in T cells from these mice. The interaction of CD8α with Lck is critical for positive selection, because Lck-/- mice expressing a mutated transgenic Lck incapable of interacting with CD8 failed to develop mature CD8 T cells (55). The CD8-Lck interaction is also necessary for negative selection (55).
More generally, the association of Lck with either the CD4 or CD8 coreceptor has been reported to underlie thymic selection of an MHC-restricted TCR repertoire (56). It was proposed that only MHC ligands can activate productive TCR signaling by co-engagement of TCR and Lck-associated coreceptors, but that non-MHC ligands that fail to engage coreceptors cannot activate Lck and consequent TCR signaling (57). Thus, DP thymocytes bearing MHC-independent TCRs cannot be signaled and subsequently die of neglect. This hypothesis was predicated on limiting amounts of coreceptors such that no free Lck is available in DP cells (58). Experimental data showed that TCRs in mice lacking both coreceptors and MHC possessed antibody-like specificities with no MHC dependence (57;59). Moreover, mice in which Lck bears mutations of the two cysteines that mediate interaction with CD4 and CD8 in the thymus generated an MHC-independent TCR repertoire, and thymic selection of those TCRs depended on coreceptor-non-associated Lck but not on MHC (56).
The lineage choice of a DP cell for either the CD4+ or CD8+ fate depends on the MHC restriction specificity of its TCR, with MHC1-restricted T cells developing into CD8 cells and MHCII-restricted T cells developing into CD4 cells (60). A “kinetic signaling model” has been proposed to explain the mechanism of lineage choice, which involves changes in coreceptor transcription driven by the persistence or termination of TCR-mediated positive selection signaling and by IL-7 receptor signaling [reviewed in (61)]. For CD8α, transcription factors including RUNX3 and Ikaros act on developmental stage-specific enhancer elements to induce its expression in CD8 T cells (62-64).
The alfalfa mutation lies within CDR1 that mediates binding to pMHC1. It is likely that the alfalfa mutation impairs the binding of CD8αβ to pMHC1, leading to diminished numbers and frequencies of CD8 T cells in the blood as a result of defective positive selection.
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|Science Writers||Eva Marie Y. Moresco|
|Authors||Ming Zeng, Bruce Beutler|
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