Expression of activating receptors on natural killer cells from AIDS-related lymphoma patients

abstract: ...Background Abnormal NK phenotype and cytotoxic functions have been described in acute myeloid leukemia, chronic lymphocytic leukemia, myeloma and myelodysplastic syndromes. Defective NK cytotoxicity is due to decreased expression of the Natural Cytotoxicity Receptors (NCRs), 2B4/CD244/p38, or NKG2D. This prompted us to test the expression of these molecules on circulating NK cells from patients with AIDS-related lymphomas (RL) in comparison with HIV+patients without lymphoma, healthy subjects and HIV-negative patients with lymphoma. Methods Blood samples were analyzed by flow cytometry for NCRs, 2B4/CD244/p38 and NKG2D expression on NK cells defined as CD3-/CD56+ lymphocytes. We also analyzed by quantitative PCR specific RNA for NKp30/NCR3 and NKp46/NCR1. Results We could not detect any defect in NKp46/NCR1 expression between all groups. NKp44/NCR2, NKp30/NCR3 and NKG2D had lower expression in AIDS-RL in comparison with HIV+patients without lymphoma when compared to patients with similar (>0.3G/L) CD4+ lymphocyte levels. Expression of 2B4/CD244/p38 was lower in AIDS-RL than in HIV-negative lymphoma. Comparison of specific NKp30/NCR3 and NKp46/NCR1 RNA showed increased steady state levels, despite decreased surface expression for NKp30/NCR3, suggesting abnormal post-transcriptional regulatory mechanisms. Conclusions We show a more pronounced defect in NK activating molecule when HIV infection is associated with lymphoma than when only one condition (HIV positivity or lymphoma) is present. Defective NK phenotype, in addition to CD4+ depletion and dysfunction, may participate to the increased incidence of lymphoma in HIV patients.

... NKp30/NCR3 and NKp46/NCR1. Results We could not detect any defect in NKp46/NCR1 expression between all groups. NKp44/NCR2, NKp30/NCR3 and NKG2D had lower expression in AIDS-RL in comparison with HIV+patients without lymphoma when compared to patients with similar (>0.3G/L) CD4+ lymphocyte levels. Expression of 2B4/CD244/p38 was lower in AIDS-RL than in HIV-negative lymphoma. Comparison of specific NKp30/NCR3 and NKp46/NCR1 RNA showed increased steady state levels, despite decreased surface

... hypothesis, absent or deficient expression of HLA-class-I molecule activates NK if an additional activating signal is delivered by the natural cytotoxicity receptors (NCR) NKp30/NCR3, NKp44/NCR2 or NKp46/NCR1, 2B4/CD244/p38 and NKG2D. Deficient NK functions interfere with the anti-tumor response: 1) during treatment, via decreased efficiency of anti-CD20 antibody-driven cell cytotoxicity (ADCC) [ 3 5 ] 2) during the complete remission phase by favoring residual HLA-class-I negative lymphoma cells to

.... Material and Methods). When significant, statistical results are indicated with the corresponding p-value. The number of analyzed patients was: AIDS-RL/CD4<300/mm3=20, AIDS-RL/CD4>300/mm3=11, HIV+<300 CD4/mm3=12, HIV+>400 CD4/mm3=44, non AIDS-RL lymphoma = 33, control HS = 19. NK activating receptors expression (Figure 1 -Panel B, C, D, E, F) No difference in NKp46/NCR1 expression was observed (Figure 1 , panel B, p>0.05, NS). The analysis of NKp44/NCR2 expression, an activating receptor only expressed on activated NKs (Figure 1 , panel C) showed no difference between AIDS-RL and HIV-negative lymphoma patients (p>0.05, NS) and between AIDS-RL and HIV patients without lymphoma but with <300 CD4/mm 3 patients (p>0.05, NS). However, AIDS-RL with >300 CD4+ lymphocytes/mm 3 expressed lower NKp44/NCR2 than HIV+patients without lymphoma with >300 CD4+ lymphocytes/mm 3 (MFIr median (M)=1.52; interquartile range (IQR)[1.24-1.850] vs M=1.80 IQR[1.540-2.110], p=0.011) and than HS (M=1.75 IQR[1.650-2.000], p=0.006). In spite of a very high NKp44/NCR2 expression by one HIV+lymphoma with <300 CD4+ lymphocytes/mm 3 (MFIr =6.21), this group tended to express lower NKp44/NCR2 than HIV+patients with >300 CD4+ lymphocytes/mm 3 (M=1.42 IQR[1.320-1.765] vs 1.80[1.543-2.115], p=0.06). HIV-negative lymphoma patients expressed more NKp44/NCR2 than HIV+patients without lymphoma and >300 CD4+ lymphocytes/mm 3 (M=1.48 IQR[1.330-1.690] vs 1.80[1.543-2.115], p=0.02) or HS (M=1.75[1.650-2.000], p=0.002). There was

... (Panel B) was overexpressed in AIDS-RL patients (normalized ratio >2 for the 7 patients analyzed). No significant RNA level was detected for NKp44/NCR2, a results in line with normal physiology since this molecule is only expressed by stimulated NKs (data not shown). Discussion The total NK cells count in patients with <300 CD4+ lymphocytes/mm 3 was lower in AIDS-RL in comparison with the other groups, suggesting a poor prognosis as shown in low or high grade HIV-negative lymphomas [ 12 , 13 ]. Low circulating counts concerned the NK CD56 bright and CD56 low subsets, while the ineffective CD56 negative subpopulation was elevated in AIDS-RL (data not shown). Regarding the NCR we found no difference in NKp46/NCR1 expression in the different groups but, in contrast, a significant decrease in both NKp44/NCR2 and NKp30/NCR3 was observed in AIDS-RL with >300 CD4/mm 3 in comparison with HIV+patients with comparable CD4+ lymphocytes. Thus in moderately immune-suppressed patients the development of lymphoma

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Gene: NCR2 - natural cytotoxicity triggering receptor 2 - (NCBI)

Protein : 1hkf

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