User:JulieAuger/CD1-restricted T cells

Cd1-restricted T cells are part of the unconventional T cell family, they do not recognize foreign antigens, they are stimulated by exposure to CD1+ antigen presenting cells (APCs) alone. Many CD1-restricted T cells are autoreactive and are rapidly stimulated to carry out helper and effector functions upon interaction with CD1-expressing antigen-presenting cells. CD1-restricted T cells regulate host defence, antitumor immunity and the balance between tolerance and autoimmunity. CD1-restricted T cells can be divided into 2 functional groups:


 * those that produce mainly T helper type 1 (TH1) cytokines


 * those that potently produce both TH1 and TH2 cytokine

CD1-restricted T cells can also be divided according to their CD1 molecule. Humans express four CD1 isoforms divided in 2 groups: group 1 CD1 (CD1a, CD1b, and CD1c), group 2 CD1 (CD1d).

Group 1 CD1-restricted T cells Group 1
Group 1 CD1-restricted T cells express diverse αβ T-cell receptors (TCRs). They can undergo clonal expansion in the periphery after recognition of stimulatory self-lipids or exogenous lipid antigens derived from bacteria. CD1–restricted T cells produce TH1, IFN-γ and TNF-α cytokines and are cytolytic. They can induce TNF-α dependent dentritic cells maturation. Many group 1 CD1–restricted T cells are autoreactive, and autoreactivity is enhanced by stimulation through pattern recognition receptors (PRRs). CD1a-autoreactive cells are present at high frequencies in blood and skin. CD1a-restricted autoreactive T cells expressed diverse TCR and produce interleukin 22 (IL-22), moreover CD1a recognizes skin lipid antigens and is highly expressed on Langerhans cells. This suggest that these T cells play a role in dermal immunity. Self-reactive CD1b-restricted T cells can acquire the phenotype of T helper 17 (TH17) cells and recruit neutrophils. CD1c autoreactive cells has been identified to play a role in tumor detection. CD1–restricted T cells can kill immature dentritic cells that are infected.

CD1d restricted natural killer T cells or group 2 CD1-restricted T cells Group 1
CD1d-restricted NKT cells contribute to host defence by influencing the function of macrophages, dentritic cells, B cell s and Natural Killer cells. They also contribute to tumor immunosurveillance and can mediate tumor rejection via interleukin 12 (IL-12) production, Natural Killer or T cell activation, or direct cytolysis

CD1d-restricted NKT cells are divided into 2 groups:


 * Type I NKT cells also called ‘invariant NKT cells’ or ‘iNKT cells’: express an invariant TCRα chain and a limited, but not invariant, range of TCRβ chains.
 * Type II NKT cells also called ‘diverse NKT cells’: use αβ TCRs that do not conform to the TCR motifs described above. Their TCR sequence is more variable than iNKT cells

Type I NKT cells are less frequent in humans than in mice (1–3% of T cells in most mouse tissues, 50% in mouse liver and bone marrow, and approximately 0.1% of T cells in human blood). All type I NKT cells recognize the marine sponge-derived glycolipid, α-galactosylceramide (α-GalCer). After the encounter with the antigen Type I NKT cells rapidly become effector cells (minutes to hours) and produce many cytokines. These T cells also have a cytotoxic activity against CD1d+ tumor targets. Furthermore, type I NKT cells upregulate CD154 and produce many cytokines which activates DCs and increase expression of the costimulatory molecules CD80 and CD86 and produce IL-12. This led to a better presentation of antigen to MHC-restricted adaptive T cells, activation of NK cells and enhanced B cell responses. Thus, NKT cells can promote downstream innate and adaptive immune responses and, in turn, enhance protection against infection and cancer. Human iNKT cells comprise phenotypically and functionally distinct subsets: CD4+, a small fraction of CD4−CD8αα+ and double negative cells. The CD4+ subset can produce TH2-type cytokines whereas both the CD4+ and CD4− subsets can secrete TH1-type cytokines and cytotoxic molecules such as perforin or granzyme B.

Type II NKT cells recognize CD1d but lack the highly conserved TCRα chain and reactivity to α-GalCer that classify type I NKT cells. Some type II NKT cells recognize the mammalian glycolipid sulfatide (produced at high concentrations in neuroendocrine tissue) phospholipid antigen lysophosphatidylcholine and some other phospholipid, and lysophospholipid antigens, including phosphatidylglycerol, and phosphatidylinositol of microbial and mammalian origin. They can also sense gene products of hepatitis B virus by detecting lysophosphatidylethanolamine generated through the cleavage of phosphatidylethanolamine by virus-induced phospholipases. Even non-lipidic small molecules, such as PPBF (phenyl 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonate), are antigenic for some type II NKT cells. Thus, type II NKT cells seem to recognize diverse antigens presented by CD1d and given that these cells seem to be more abundant than type I NKT cells in humans, it is important to understand their roles and therapeutic potential.