CD99 Signals Caspase-Independent T Cell Death

Abstract

Death signaling by Fas and TNF receptors plays a major role in the control of activated mature T cells. However, the nature of the death receptors, which may be used by the immune system to control T cells that have not acquired susceptibility to Fas ligand or TNF, is not established. In this study, we demonstrate that engagement of distinct epitopes on CD99 rapidly induces T cell death by a novel caspase-independent pathway. A new mAb to these CD99 epitopes, Ad20, induces programmed cell death of transformed T cells as determined by morphological changes, phosphatidylserine exposure on the cell surface, and uptake of propidium iodide. In general, ligation of CD99 induced kinetically faster and more profound death responses as compared with the impact of anti-Fas and TNF-related apoptosis-inducing ligand (TRAIL). Ad20-induced programmed cell death was observed with seven of eight T cell lines examined, and notably, only two of these were distinctly responsive to anti-Fas and TRAIL. CD99-mediated death signaling proceeded independently of functional CD3, CD4, CD45, and p56lck, revealed distinctions from CD47-mediated T cell death responses, and was not influenced by interference with CD47 signaling. In contrast to the effect on transformed T cell lines, Ad20-induced death responses were not observed with normal peripheral T cells. Thus, our data suggest that CD99 is linked to a novel death pathway that may have biologic relevance in control of early T cells.

The Contraction Phase of Virus-Specific CD8+ T Cells Is Unaffected by a Pan-Caspase Inhibitor

“…Similar results were observed for CD8 ϩ T cells specific for the remaining three epitopes shown in Fig. 4, and also for CD4 ϩ T cells specific for the GP 61 and NP 309 epitopes (not shown). Any differences observed were not statistically significant.…”

“…In brief, cells from blood, lymph nodes, or spleens of LCMV-infected or naive mice were isolated as described above, then were incubated in round-bottom 96-well plates at 37°C, 5% CO 2 , for 5-7 h in the presence or absence of peptide in RPMI 1640 (containing 5-10% FBS, 100 M 2-ME, L-glutamine, and antibiotics). The peptides, used at a final concentration of 1-2 g/ml, represent dominant and subdominant CD8 ϩ T cell epitopes from LCMV: NP 118 [61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80] and NP 309 -328 (both H-2A b ). Brefeldin A (Sigma) was added to a final concentration of 5 g/ml.…”

Sex‐specific association of a common variant of the XG gene with autism spectrum disorders

“…It has been suggested that the PARs may harbor genes for other psychiatric disorders including schizophrenia and bipolar affective disorders [Crow et al, 1994;Saito et al, 2000;Muller et al, 2002;Lencz et al, 2007]; however, they have been largely neglected in systematic genome-wide linkage and association studies [Flaquer et al, 2008[Flaquer et al, , 2009. For example, the Illumina HumanHap550 genotyping platform does not include any SNP markers in the PAR1 region in or near XG/ XGPY2 at chromosome Xp22.33/ Yp11.31 where our novel significant association signal was identified.The XG gene encodes human red blood cell Xg a antigen and is tightly linked to an adjacent gene, CD99, which encodes CD99 antigen, a T-cell surface protein, expressed on all leukocytes, which plays an important role in immunology, including leukocyte migration and activation, T-cell adhesion, and caspase-independent T-cell death [Hahn et al, 1997;Pettersen et al, 2001;Oh et al, 2007;Dufour et al, 2008]. There is emerging evidence that an abnormal immune response may be involved in some forms of ASD, in the form of decreased peripheral lymphocyte counts, incomplete T cell activation, dysregulated apoptosis mechanisms, and imbalanced serum Ig levels [Ashwood et al, 2006].…”

CD99 type II is a determining factor for the differentiation of primitive neuroectodermal cells

“…Originally, CD99 was described as a human thymus leukemia antigen, Ewing's sarcomaspecific membrane marker molecule, and a putative adhesion molecule (termed E2) involved in spontaneous rosette formation of T cells with erythrocytes (Bernard et al, 1988;Aubrit et al, 1989;Gelin et al, 1989). In the studies using monoclonal antibodies (mAbs) against CD99 as stimulatory ligands, engagement of CD99 led to homotypic aggregation and death of thymocytes and Jurkat T cells (Bernard et al, 1995;Bernard et al, 1997;Hahn et al, 1997;Pettersen et al, 2001) and induced up-regulation of T cell receptor (Waclavic et al, 1998) and major histocompatibility complex molecules on the cell surface (Choi et al, 1998;Kim et al, 2003).…”