PMID- 12806026
OWN - NLM
STAT- MEDLINE
DCOM- 20040323
LR  - 20180705
IS  - 1537-744X (Electronic)
IS  - 2356-6140 (Print)
IS  - 1537-744X (Linking)
VI  - 2
DP  - 2002 Feb 12
TI  - Soluble HLA class I molecules/CD8 ligation trigger apoptosis of CD8+ cells by 
      Fas/Fas-ligand interaction.
PG  - 421-3
AB  - The human major histocompatibility complex (HLA) encodes two sets of HLA class I 
      molecules, which have been termed class Ia (or classical) and class Ib (or 
      nonclassical) molecules. The class Ia molecules include the gene products of 
      HLA-A, HLA-B, and HLA-C loci and are characterized by broad tissue expression and 
      by a high degree of polymorphism. The class Ib molecules include the gene 
      products of HLA-E, HLA-F, and HLA-G loci and are characterized by a restricted 
      tissue distribution and by limited polymorphism. Besides being expressed on 
      nucleated cells, classical and nonclassical HLA class I molecules are present in 
      serum in soluble form (sHLA-I). The serum level of sHLA-I molecules is 
      significantly increased in a variety of physiological and pathological conditions 
      such as pregnancy, acute rejection episodes following organ allografts, acute 
      graft-versus-host-disease (GVHD) following bone marrow transplantation, 
      autoimmune diseases, viral infections, and malignant melanoma. Because of the 
      statistically significant association with clinical parameters, the level of 
      sHLA-I antigens has been suggested to represent a useful marker to predict the 
      evolution of viral infections and to monitor the clinical course of allografts. 
      Moreover, elevated levels of functional sHLA-I and soluble Fas-ligand molecules 
      have been detected by our group in blood components and might play a role in the 
      immunomodulatory effect of autologous and allogeneic transfusions. Several lines 
      of evidence suggest that sHLA-I molecules are immunologically functional and may 
      play an immunoregulatory role. In fact, they have been shown to elicit antibodies 
      in both allogeneic and xenogeneic combinations, to inhibit the activity of 
      alloreactive cytotoxic T lymphocytes (CTL), and to induce apoptosis in 
      alloreactive and virus-specific CTL, in activated autologous and allogeneic CD8+ 
      T cells, and in CD8+ NK cells. There is general agreement about the mechanism 
      underlying the inhibition of CTL activity by sHLA antigens. This inhibition 
      appears to be mediated by interactions of sHLA-I antigens a1 and a2 domains with 
      T cell receptor (TCR). By contrast, there is conflicting information about the 
      mechanism underlying induction of apoptosis of activated T cells by sHLA-I 
      antigens. Several authors reported that sHLA-I molecules induced apoptosis of 
      alloreactive CD8+ cytotoxic T lymphocytes through interaction with their TCR. 
      However, our own data and those other groups indicate that classical and 
      nonclassical sHLA-I molecules trigger Fas/Fas-ligand mediated apoptosis of 
      phytohemoagglutinin (PHA)-activated and virus-specific CD8+ T lymphocytes as well 
      as of CD8+ NK cells by interacting with CD8 coreceptor. Recently, we performed a 
      series of experiments in our laboratory to clarify the intracellular mechanism(s) 
      leading to Fas-ligand upregulation and secretion. These unpublished data indicate 
      that sHLA-I/CD8 ligation elicits the phosphorylation of p56lck protein thyrosin 
      kinase (PTK) associated with CD8 cytoplasmic domain in the absence of any other 
      TCR-derived signal, the activation of syk-like ZAP-70 PTK and protein kinase C, 
      and extracellular calcium influx. Then, activation and nuclear translocation of 
      NF-kB and NF-AT occurs, leading to Fas-ligand mRNA transcription and soluble 
      Fas-ligand secretion, which delivers the death signal. Interestingly, soluble 
      Fas-ligand secretion and CD8+ cell apoptosis, but not CD8+ cell cytolitic 
      activity, are completely inhibited by Cyclosporin A, which specifically blocks 
      the activation of the calcineurin/calmodulin pathway. Taken together, these data 
      suggest that sHLA-I molecules are involved in a signal-transduction pathway 
      leading to Fas-ligand expression, soluble Fas-ligand secretion, and CD8+ cells 
      apoptosis.
FAU - Puppo, Francesco
AU  - Puppo F
AD  - Department of Internal Medicine (DIMI), Viale Benedetto XV, n. 6, 16132 Genoa, 
      Italy. metclin@unige.it
FAU - Contini, Paola
AU  - Contini P
FAU - Ghio, Massimo
AU  - Ghio M
FAU - Indiveri, Francesco
AU  - Indiveri F
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20020212
PL  - United States
TA  - ScientificWorldJournal
JT  - TheScientificWorldJournal
JID - 101131163
RN  - 0 (CD8 Antigens)
RN  - 0 (FASLG protein, human)
RN  - 0 (Fas Ligand Protein)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Recombinant Proteins)
RN  - 0 (fas Receptor)
SB  - IM
MH  - Apoptosis/*drug effects
MH  - CD8 Antigens/*pharmacology
MH  - CD8-Positive T-Lymphocytes/*drug effects
MH  - Fas Ligand Protein
MH  - Histocompatibility Antigens Class I/*pharmacology
MH  - Humans
MH  - Lymphocyte Subsets/*drug effects
MH  - Membrane Glycoproteins/*metabolism
MH  - Recombinant Proteins/*pharmacology
MH  - Solubility
MH  - fas Receptor/*metabolism
PMC - PMC6009369
EDAT- 2003/06/14 05:00
MHDA- 2004/03/24 05:00
PMCR- 2002/02/12
CRDT- 2003/06/14 05:00
PHST- 2003/06/14 05:00 [pubmed]
PHST- 2004/03/24 05:00 [medline]
PHST- 2003/06/14 05:00 [entrez]
PHST- 2002/02/12 00:00 [pmc-release]
AID - 950120 [pii]
AID - 10.1100/tsw.2002.122 [doi]
PST - epublish
SO  - ScientificWorldJournal. 2002 Feb 12;2:421-3. doi: 10.1100/tsw.2002.122.