STRUCTURE

CD8 is a transmembrane glycoprotein composed by two disulfide-linked chains in its native state.^1-4 CD8 can be a homodimer of CD8α (CD8αα) or a heterodimer of CD8α and CD8β (CD8αβ).^2-4 CD8α and CD8β belong to the Ig superfamily and display an IgV-like domain in the extracellular part followed by a stalk region.^1,5 CD8α contains a Lck binding domain in the cytoplasmic tail.⁶ CD8 also exists in a soluble form.⁷

1. Littman DR, Thomas Y, Maddon PJ, Chess L, Axel R. The isolation and sequence of the gene encoding T8: a molecule defining functional classes of T lymphocytes.Cell. 1985;40:237-46.
2. Norment AM, Littman DR. A second subunit of CD8 is expressed in human T cells. EMBO J. 1988;7:3433-9.
3. Shiue L, Gorman SD, Parnes JR. A second chain of human CD8 is expressed on peripheral blood lymphocytes. J Exp Med. 1988;168:1993-2005.
4. Moebius U, Kober G, Griscelli AL, Hercend T, Meuer SC. Expression of different CD8 isoforms on distinct human lymphocyte subpopulations. Eur J Immunol. 1991 ;21:1793-800.
5. Nakauchi H, Shinkai Y, Okumura K. Molecular cloning of Lyt-3, a membrane glycoprotein marking a subset of mouse T lymphocytes: molecular homology to immunoglobulin and T-cell receptor variable and joining regions. Proc Natl Acad Sci U S A. 1987;84:4210-4.
6. Turner JM, Brodsky MH, Irving BA, Levin SD, Perlmutter RM, Littman DR. Interaction of the unique N-terminal region of tyrosine kinase p56lck with cytoplasmic domains of CD4 and CD8 is mediated by cysteine motifs. Cell. 1990;60:755-65.
7. Fujimoto J, Levy S, Levy R. Spontaneous release of the Leu-2 (T8) molecule from human T cells. J Exp Med. 1983;158:752-66.

LIGANDS

Extracellular

MHC class I.¹ In addition, CD8αα can bind to thymus leukemia antigen.²

Intracellular associate molecules

Lck³, LAT⁴ and CD3δ.⁵

1. Janeway CA Jr. The T cell receptor as a multicomponent signalling machine: CD4/CD8 coreceptors and CD45 in T cell activation. Annu Rev Immunol. 992;10:645-74.
2. Leishman AJ, Naidenko OV, Attinger A, Koning F, Lena CJ, Xiong Y, Chang HC, Reinherz E, Kronenberg M, Cheroutre H. T cell responses modulated through interaction between CD8alphaalpha and the nonclassical MHC class I molecule,  TL. Science. 2001;294:1936-9.
3. Turner JM, Brodsky MH, Irving BA, Levin SD, Perlmutter RM, Littman DR. Interaction of the unique N-terminal region of tyrosine kinase p56lck with cytoplasmic domains of CD4 and CD8 is mediated by cysteine motifs. Cell. 1990;60:755-65.
4. Bosselut R, Zhang W, Ashe JM, Kopacz JL, Samelson LE, Singer A. Association of the adaptor molecule LAT with CD4 and CD8 coreceptors identifies a new coreceptor function in T cell receptor signal transduction. J Exp Med. 1999;190:1517-26.
5. Doucey MA, Goffin L, Naeher D, Michielin O, Baumgärtner P, Guillaume P, Palmer E, Luescher IF. CD3 delta establishes a functional link between the T cell receptor and CD8. J Biol Chem. 2003;278:3257-64.

CD8 is present on most thymocytes.¹ Cytotoxic αβ T cells predominantly display CD8αβ but can also express CD8αα.^2-3 NK cells, γδ T cells, intestinal intraepithelial lymphocytes and monocytes only express CD8αα.^2,4-5 Furthermore, a subset of lymphoid tissue-resident DCs in mice also express CD8α.⁶

1. Germain RN. T-cell development and the CD4-CD8 lineage decision. Nat Rev Immunol. 2002;2:309-22.
2. Terry LA, DiSanto JP, Small TN, Flomenberg N. Differential expression and regulation of the human CD8 alpha and CD8 beta chains. Tissue Antigens. 1990;35:82-91.
3. Moebius U, Kober G, Griscelli AL, Hercend T, Meuer SC. Expression of different CD8 isoforms on distinct human lymphocyte subpopulations. Eur J Immunol.   1991;21:1793-800.
4. Leishman AJ, Naidenko OV, Attinger A, Koning F, Lena CJ, Xiong Y, Chang HC, Reinherz E, Kronenberg M, Cheroutre H. T cell responses modulated through interaction between CD8alphaalpha and the nonclassical MHC class I molecule,  TL. Science. 2001;294:1936-9.
5. Gibbings DJ, Marcet-Palacios M, Sekar Y, Ng MC, Befus AD. CD8 alpha is expressed by human monocytes and enhances Fc gamma R-dependent responses. BMC Immunol. 2007;8:12.
6. Shortman K, Heath WR. The CD8+ dendritic cell subset. Immunol Rev. 2010;234:18-31.

CD8 is a co-receptor that binds to MHC class-I and participates in cytotoxic T cell activation.¹ During thymic development, CD8 is necessary for thymocyte selection.²

On monocytes, CD8 ligation improve FcR-dependent activation and TNF release.³ Interaction of CD8αα with thymus leukemia antigen leads to cytokine production on intraepithelial lymphocytes.⁴

1. O'Rourke AM, Mescher MF. The roles of CD8 in cytotoxic T lymphocyte function. Immunol Today. 1993;14:183-8.

2. Zúñiga-Pflücker JC, Jones LA, Longo DL, Kruisbeek AM. CD8 is required during positive selection of CD4-/CD8+ T cells. J Exp Med. 1990;171:427-37.

3. Gibbings DJ, Marcet-Palacios M, Sekar Y, Ng MC, Befus AD. CD8 alpha is expressed by human monocytes and enhances Fc gamma R-dependent responses. BMC Immunol. 2007;8:12.
4. Leishman AJ, Naidenko OV, Attinger A, Koning F, Lena CJ, Xiong Y, Chang HC, Reinherz E, Kronenberg M, Cheroutre H. T cell responses modulated through interaction between CD8alphaalpha and the nonclassical MHC class I molecule,  TL. Science. 2001;294:1936-9.

Cell marker

Marker of cytotoxic T cells.¹ CD8 is also a useful marker for diagnosis of lymphoproliferative disorders.^2-3

1. Terry LA, DiSanto JP, Small TN, Flomenberg N. Differential expression and regulation of the human CD8 alpha and CD8 beta chains. Tissue Antigens. 1990;35:82-91.
2. Béné MC, Nebe T, Bettelheim P, Buldini B, Bumbea H, Kern W, Lacombe F, Lemez P, Marinov I, Matutes E, Maynadié M, Oelschlagel U, Orfao A, Schabath R, Solenthaler M, Tschurtschenthaler G, Vladareanu AM, Zini G, Faure GC, Porwit A. Immunophenotyping of acute leukemia and lymphoproliferative disorders: a consensus proposal of the European LeukemiaNet Work Package 10. Leukemia. 2011;25:567-74.
3. van Dongen JJ, Lhermitte L, Böttcher S, Almeida J, van der Velden VH, Flores-Montero J, Rawstron A, Asnafi V, Lécrevisse Q, Lucio P, Mejstrikova E, Szczepański T, Kalina T, de Tute R, Brüggemann M, Sedek L, Cullen M, Langerak AW, Mendonça A, Macintyre E, Martin-Ayuso M, Hrusak O, Vidriales MB, Orfao A; EuroFlow Consortium (EU-FP6, LSHB-CT-2006-018708). EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes. Leukemia. 2012;26:1908-75.

Therapeutic

To our knowledge, there are no monoclonal antibodies targeting CD8 used in the clinical practice. However, administration of anti-CD8 antibodies has been effective in rodent models of autoimmune glomerulonephritis¹, spontaneous chronic polyarthritis², type 1 diabetes³ and transplantation.⁴

1. Reynolds J, Norgan VA, Bhambra U, Smith J, Cook HT, Pusey CD. Anti-CD8 monoclonal antibody therapy is effective in the prevention and treatment of experimental autoimmune glomerulonephritis. J Am Soc Nephrol. 2002;13:359-69.
2. Raposo BR, Rodrigues-Santos P, Carvalheiro H, Agua-Doce AM, Carvalho L, Pereira da Silva JA, Graça L, Souto-Carneiro MM. Monoclonal anti-CD8 therapy induces disease amelioration in the K/BxN mouse model of spontaneous chronic polyarthritis. Arthritis Rheum. 2010;62:2953-62.
3. Phillips JM, Parish NM, Raine T, Bland C, Sawyer Y, De La Peña H, Cooke A. Type 1 diabetes development requires both CD4+ and CD8+ T cells and can be reversed by non-depleting antibodies targeting both T cell populations. Rev Diabet Stud. 2009;6:97-103.
4. Newell KA, He G, Hart J, Thistlethwaite JR Jr. Treatment with either anti-CD4 or anti-CD8 monoclonal antibodies blocks alphabeta T cell-mediated rejection of intestinal allografts in mice. Transplantation. 1997;64:959-65.