Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: CD8A
SNOMEDCT: 766983005;
Cytogenetic location: 2p11.2 Genomic coordinates (GRCh38): 2:86,784,605-86,808,396 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p11.2 | Immunodeficiency 116 | 608957 | Autosomal recessive | 3 |
Comparative structural and functional studies of mouse and human T-cell antigens showed that human cytotoxic-suppressor T cells have a molecule homologous to the mouse Lyt-2,Lyt-3 molecule (Ledbetter et al., 1981). The human homolog of Lyt-2,Lyt-3 is termed LEU2. It is selectively expressed on a subset of T cells and in structure is a multimeric macromolecule composed of individual disulfide-bonded subunits. LEU2, or T8, is expressed by most T lymphocytes with cytotoxic or suppressor function. The molecule appears to be composed of multimers of a 32-kD and a 45-kD polypeptide in thymocytes and of a 32-kD polypeptide in peripheral blood lymphocytes. LEU2 (like its proposed murine homolog Lyt-2) may play a role in target-cell recognition. Kavathas et al. (1984) isolated genomic and cDNA clones for LEU2. Giblin et al. (1989) showed that through alternative splicing of mRNA, an exon encoding a transmembrane domain of CD8 is deleted. This gives rise to a 30-kD molecule that is secreted and exists as a monomer. The splicing pattern in man differs from that found in the mouse CD8 gene. This mRNA is also alternatively spliced, but an exon encoding a cytoplasmic region is deleted, giving rise to a cell surface molecule that differs in its cytoplasmic tail from the protein encoded by the longer mRNA. Neither protein is secreted. This is an example of the different splicing patterns of 2 homologous mouse and human genes giving rise to different proteins. This represents 1 mechanism of generating diversity during speciation.
The classical paradigm for dendritic cell function derives from the study of Langerhans cells, which predominate within skin epidermis. After an encounter with foreign agents, Langerhans cells are thought to migrate to draining lymph nodes, where they initiate T cell priming. Contrary to this view, Allan et al. (2003) showed that infection of murine epidermis by herpes simplex virus did not result in the priming of virus-specific cytotoxic T lymphocytes by Langerhans cells. Rather, the priming response required a distinct CD8A+ dendritic cell subset. Thus, Allan et al. (2003) concluded that the traditional view of Langerhans cells in epidermal immunity needs to be revisited to accommodate a requirement for other dendritic cells in this response.
Madakamutil et al. (2004) demonstrated that homodimeric alpha chains of the CD8 molecule (CD8-alpha-alpha) are transiently induced on a selected subset of CD8-alpha-beta+ T cells upon antigenic stimulation. These CD8-alpha-alpha molecules promote the survival and differentiation of activated lymphocytes into memory CD8 T cells. In the presence of CD8-alpha-alpha, activated CD8 T cells upregulate IL7R-alpha (146661) and IL2/IL15 receptor-beta (CD122; 146710). This leads to increased expression of the survival factors BCL-XL (600039) and BCL2 (151430), and to the survival of these cells, enabling them to become memory T cells (Kim and Flavell, 2004). Thus, Madakamutil et al. (2004) concluded that memory precursors can be identified among primary effector cells and are selected for survival and differentiation by CD8-alpha-alpha.
CD8 T lymphocytes recognize peptides of 8 to 10 amino acids presented by class I molecules of the major histocompatibility complex. Vigneron et al. (2004) found that CD8 T lymphocytes were able to recognize a nonameric peptide on melanoma cells that comprises 2 noncontiguous segments of melanocytic glycoprotein gp100(PMEL17) (155550). The production of this peptide involves the excision of 4 amino acids and splicing of the fragments. This process was reproduced in vitro by incubating a precursor peptide of 13 amino acids with highly purified proteasomes. Splicing appears to occur by transpeptidation involving an acyl-enzyme intermediate. Vigneron et al. (2004) concluded that their results reveal an unanticipated aspect of the proteasome function of producing antigenic peptides.
Janssen et al. (2005) explored the instructional program that governs the secondary response of CD8+ T cells and found that helpless cells (which, when primed in the absence of CD4+ T cells, can mediate effector functions such as cytotoxicity and cytokine secretion upon restimulation but do not undergo a second round of clonal expansion) undergo death by activation-induced cell death upon secondary stimulation. This death is mediated by TRAIL (603598). Regulation of TRAIL expression can therefore account for the role of CD4+ (186940) T cells in the generation of CD8+ T cell memory and represents a novel mechanism for controlling adaptive immune responses.
Williams et al. (2006) showed that although IL2 (147680) signaling to pathogen-specific CD8+ T cells affects the number of developing effector and memory cells very little, it is required for the generation of robust secondary responses. This is not due to an altered T cell receptor repertoire development or selection, and does not reflect an acute requirement for IL2 during secondary activation and expansion. Rather, Williams et al. (2006) demonstrated a previously unappreciated role for IL2 during primary infection in programming the development of CD8+ memory T cells capable of full secondary expansion.
Chang et al. (2007) observed unequal partitioning of signaling proteins and asymmetric cell division in fluorescently labeled Cd8-positive naive transgenic mouse T cells responding to a microbe antigen. Components of the immunologic synapse, where the T cell and antigen-presenting cell meet, colocalized with 1 microtubule-organizing center (MTOC). Scribble (SCRIB; 607733) and protein kinase C-zeta (PRKCZ; 176982), ancestral regulators of asymmetric cell division, localized to the MTOCs proximal to and opposite the synapse, respectively, during mitosis. Numb (603728), Ifng (147570), and Ifngr (107470) also localized to the MTOC proximal to the synapse. Cells expressing high levels of Cd8 and low levels of the memory T-cell marker Cd62l (SELL; 153240) were larger, more granular, and located at the synaptic pole. Smaller, less granular daughter cells expressing low Cd8 and high Cd62l were found at the distal pole. Flow cytometric sorting of putative proximal and distal daughter cells showed that distal daughter cells provided better protection than proximal daughter cells to naive secondary recipient mice when challenged 30 days after adoptive cell transfer. However, proximal daughter cells were as good or better than their distal counterparts when animals were challenged immediately after transfer. Chang et al. (2007) proposed that the immunologic synapse may help coordinate asymmetric cell division with simultaneous assignment to effector and memory populations during mitosis. In a commentary, Littman and Singh (2007) suggested additional experiments to test this hypothesis.
In a screen for endogenous tumor-associated T-cell responses in a primary mouse model of prostatic adenocarcinoma, Savage et al. (2008) identified a naturally arising CD8+ T-cell response that is reactive to a peptide derived from histone H4 (602822). Despite the ubiquitous nature of histones, T cell recognition of histone H4 peptide was specifically associated with the presence of prostate cancer in these mice. Thus, Savage et al. (2008) concluded that the repertoire of antigens recognized by tumor-infiltrating T cells is broader than previously thought and includes peptides derived from ubiquitous self antigens that are normally sequestered from immune detection.
Combining computer modeling and single-cell measurements, Feinerman et al. (2008) examined how endogenous variation in the expression levels of signaling proteins might affect antigen responsiveness during T-cell activation. They found that the CD8 coreceptor fine-tuned activation thresholds, whereas the soluble hematopoietic phosphatase-1 (SHP1; 176883) digitally regulated cell responsiveness. Stochastic variation in expression of these proteins generated substantial diversity of activation within a clonal population of T cells, but coregulation of CD8 and SHP1 levels ultimately limited this very diversity. Feinerman et al. (2008) concluded that these findings revealed how eukaryotic cells can draw on regulated variation in gene expression to achieve phenotypic variability in a controlled manner.
Dai et al. (2010) noted that CD8-positive/CD122-positive T cells have been shown to function, paradoxically, as both regulatory and memory T cells. Using flow cytometric analysis, they demonstrated that mouse Cd8-positive/Cd122-positive T cells included both Pd1 (PDCD1; 600244)-positive and Pd1-negative subpopulations. Only the Pd1-positive subpopulation suppressed T-cell responses in vitro and in vivo, and this suppression occurred largely in an Il10 (124092)-dependent manner. Il10 production, in turn, was dependent on costimulatory signaling of both Cd28 (186760) and Pd1. Cd8-positive/Cd122-positive/Pd1-negative T cells mediated skin graft rejection. Dai et al. (2010) concluded that CD8-positive/CD122-positive T cells can be either regulatory or memory T cells, depending on their PD1 expression and antigen specificity.
Using cell type-specific laser capture microdissection, transcriptional profiling, and T-cell antigen receptor beta-chain (TCRB; see 186930) genotyping on sequential genital skin biopsies, Zhu et al. (2013) showed that T cells that express CD8-alpha as a homodimer at the cell surface (CD8-alpha-alpha-positive T cells) are the dominant resident population of the dermal-epidermal junction (DEJ) CD8-positive T cells that persist at the site of previous herpes simplex virus-2 (HSV2) reactivation. CD8-alpha-alpha-positive T cells located at the DEJ lack chemokine-receptor expression required for lymphocyte egress and recirculation, express gene signatures of T-cell activation and antiviral activity, and produce cytolytic granules during clinical and virologic quiescent time periods. Sequencing of the TCR beta-chain repertoire revealed that the DEJ CD8-alpha-alpha-positive T cells are oligoclonal with diverse usage of TCR variable-beta genes, which differ from those commonly described for mucosa-associated invariant T cells and natural killer T cells. Dominant clonotypes were shown to overlap among multiple recurrences over a period of 2.5 years. Episodes of rapid asymptomatic HSV-2 containment were also associated with a high CD8 effector-to-target ratio and focal enrichment of CD8-alpha-alpha-positive T cells. Zhu et al. (2013) concluded that DEJ CD8-alpha-alpha-positive T cells are tissue-resident cells that seem to have a fundamental role in immune surveillance and in initial containment of HSV2 reactivation in human peripheral tissue.
See review of gene structure by Littman (1987).
Sukhatme et al. (1985) assigned the structural gene for LEU2/T8 to chromosome 2 by means of a cDNA clone in mouse-human cell hybrids. By in situ hybridization it was found to be situated in 2p1. The LEU2/T8 gene was found to be translocated with the kappa constant immunoglobulin gene (IGKC; 147200) to chromosome 8 in a Burkitt lymphoma line carrying a t(2;8) translocation. The close linkage to kappa supports the homology of human LEU2/T8 with mouse Lyt-2,3. Bowcock et al. (1986) gave the chromosomal localization as 2p12. Weichhold et al. (1993) linked the CD8A and IGKC loci on a 3.0-Mb fragment from a partial NruI digest. A new hybridization probe located between the 2 loci provided additional linking fragments and allowed the distance to be determined as 2.0-2.2 Mb. CD8A is on the telomeric side of IGKC.
Mecucci and Van Den Berghe (1985) described a 45-year-old man with OKT8-positive T-cell lymphoma and a rearrangement involving chromosome 2: t(2;17)(p11;p11).
In a patient, noted to be born of consanguineous Spanish Gypsy parents by the authors, with immunodeficiency-116 (IMD116; 608957), de la Calle-Martin et al. (2001) identified a homozygous missense mutation in the CD8A gene (G111S; 186910.0001). His asymptomatic sisters with absence of CD8 expression were also homozygous for the mutation; the parents were heterozygous.
In a 16-year-old girl with IMD116, designated as of Spanish Gypsy descent by the authors, Mancebo et al. (2008) identified a homozygous G111S mutation in the CD8A gene. The mutation segregated with the disorder in the family. Functional studies of the variant were not performed, but laboratory studies showed a complete absence of CD8+ T cells in the patient. Double-negative (CD4-/CD8-) T cells were increased compared to controls.
In a patient, born of consanguineous Portuguese parents, with IMD116, Dumontet et al. (2015) identified a homozygous G111S mutation in the CD8A gene. The mutation segregated with the disorder in the family and was not present in the Exome Variant Server database. Functional studies of the variant were not performed.
Amrani et al. (2000) demonstrated that progression of pancreatic islet inflammation to overt diabetes in NOD mice is driven by the 'avidity maturation' of a prevailing, pancreatic beta-cell-specific T lymphocyte population carrying the CD8 antigen. This T lymphocyte population recognizes 2 related peptides, NRP and NRP-A7, in the context of H-2K(d) class I molecules of the major histocompatibility complex. As prediabetic NOD mice age, their islet-associated CD8+ T lymphocytes contain increasing numbers of NRP-A7-reactive cells, and these cells bind NRP-A7/H-2K(d) tetramers with increased specificity, increased avidity, and longer half-lives. Repeated treatment of prediabetic NOD mice with soluble NRP-A7 peptide blunts the avidity maturation of the NRP-A7-reactive-CD8+ T cell population. This inhibits the local production of T cells that are cytotoxic to beta cells, and halts the progression from severe insulitis to diabetes. Amrani et al. (2000) concluded that avidity maturation of pathogenic T cell populations may be the key event in the progression of benign inflammation to overt disease in autoimmunity.
A subset of dendritic cells (DCs) express CD8A. Traver et al. (2000) established through mouse reconstitution experiments that CD8A expression occurs in cells of both myeloid and lymphoid origin. They observed CD8A expression only in DCs that did not express Mac1 (see ITGAM; 120980). Furthermore, Traver et al. (2000) showed that transplantation of clonogenic common myeloid precursors (CMP) into Cd8a knockout mice resulted in DCs expressing both the CD8A-positive and -negative phenotypes. Functional analysis determined that CMP-derived DCs stimulated antigen-specific T cells, produced stimulatory cytokines, and initiated the mixed lymphocyte reaction. Flow cytometric analysis revealed that they expressed IL12 (161561), CCL19 (602227), and MHC2TA (600005), molecules preferentially expressed by DCs. The authors calculated that the majority of splenic DCs and half of thymic DCs should be derived from the myeloid lineage. They proposed the existence of a common progenitor for all myeloid lineages and extrathymic DCs.
Leishman et al. (2001) used tetramer analysis in a mouse model to show that thymus leukemia antigen (TL; 188850), which is expressed abundantly on intestinal epithelial cells, preferentially binds to the homotypic form of CD8A (CD8A-CD8A), in contrast to other major histocompatibility complex molecules that bind to CD8A-CD8B (186730). Flow cytometric analysis demonstrated that most intestinal intraepithelial lymphocytes (IELs), but not splenocytes, react specifically to TL tetramers. Leishman et al. (2001) concluded that CD8A-CD8A on IELs acts semiautonomously, rather than as a T-cell receptor coreceptor. They suggested that expression of CD8A-CD8A on IELs could have important regulatory effects that influence homeostasis, activation, and survival of IELs under the high antigen load of the intestine.
Sun and Bevan (2003) found that mice lacking Cd4 mounted a primary Cd8 response equal to that of wildtype mice and rapidly cleared infection with Listeria monocytogenes. However, the Cd4-deficient mice had defective memory Cd8-positive T cells over time, indicating a need for Cd4 help in promoting protective Cd8 memory development. Sun and Bevan (2003) proposed that vaccination schemes targeting only CD8 immunity may fail to provide long-term protection.
Shedlock and Shen (2003) showed that memory Cd8 cells generated in the presence of Cd4 cells responded normally in Cd4 -/- mice, whereas Cd8 cells induced in Cd4 -/- mice were defective in their recall responses to both lymphocytic choriomeningitis virus and L. monocytogenes antigens in Cd4 +/+ mice. They concluded that CD4-positive cells are required in the priming phase for functional CD8 memory, but they are dispensable during the recall response for secondary expansion.
Microbial infections, as well as dying mammalian cells, have been proposed to send a 'danger signal' to the immune system, resulting in dendritic cell maturation and presentation of antigens to T lymphocytes. Shi et al. (2003) found that uric acid was the principal low molecular weight signal released from injured mouse cells and significantly enhanced the generation of CD8-positive T-cell responses when coinjected with antigen in vivo. Elimination of uric acid by pretreatment with allopurinol or uricase (UOX; 191540), an enzyme present in rodents but not in humans, abolished the adjuvant effect of monosodium urate. Shi et al. (2003) proposed that uric acid may represent an alternative to alum adjuvants in humans, with the capacity to induce CD8 immunity.
In mice, at least 5 Cd8 cis-acting enhancers, individually or in combination, direct expression in the T-cell lineage, and deletion of specific enhancers leads to variegated expression of Cd8a/Cd8b heterodimers in double-positive thymocytes. Bilic et al. (2006) showed that Cd8 variegation due to enhancer deletion correlated with an epigenetic 'off' state, linking Cd8 enhancer function with chromatin remodeling of Cd8a and Cd8b. The zinc finger protein Mazr (ZNF278; 605165) bound the Cd8 enhancer and, via its N-terminal domain, interacted with the Ncor1 (600849) complex in double-negative thymocytes. Mazr was downregulated in double-positive and Cd8 single-positive thymocytes. Constitutive expression of Mazr during T-cell development resulted in variegated expression of Cd8 in double-positive thymocytes. Bilic et al. (2006) concluded that MAZR is a negative regulator of CD8 expression in double-negative thymocytes.
In a patient, noted as born of consanguineous Spanish Gypsy parents by the authors, with immunodeficiency-116 (IMD116; 608957), de la Calle-Martin et al. (2001) identified a homozygous c.331G-A transition in exon 2 of the CD8A gene, resulting in an amino acid substitution that they designated GLY90SER in a conserved residue in the immunoglobulin domain of the protein. Two asymptomatic sisters with absence of CD8 expression were also homozygous for the mutation; the parents were heterozygous.
In a 16-year-old girl with IMD116, noted to be of Spanish Gypsy descent by the authors, Mancebo et al. (2008) identified a homozygous c.331G-A transition in exon 2 of the CD8A gene, resulting in a gly111-to-ser (G111S) substitution. The mutation segregated with the disorder in the family. The mutation affected a highly conserved residue; functional studies of the variant were not performed. Population studies showed a carrier rate of 0.4% among individuals of Spanish Gypsy origin. Haplotype analysis indicated a founder effect in this population and suggested that the mutation arose after the entry of the Gypsy population into the Iberian peninsula in the early 15th century.
In a patient, born of consanguineous Portuguese parents, with IMD116, Dumontet et al. (2015) identified a homozygous G111S mutation in the CD8A gene. The mutation segregated with the disorder in the family and was not present in the Exome Variant Server database. Functional studies of the variant were not performed.
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