The FERM and PDZ Domain-Containing Protein Tyrosine Phosphatases, PTPN4 and PTPN3, Are Both Dispensable for T Cell Receptor Signal Transduction

PTPN3 and PTPN4 are two closely-related non-receptor protein tyrosine phosphatases (PTP) that, in addition to a PTP domain, contain FERM (Band 4.1, Ezrin, Radixin, and Moesin) and PDZ (PSD-95, Dlg, ZO-1) domains. Both PTP have been implicated as negative-regulators of early signal transduction through the T cell antigen receptor (TCR), acting to dephosphorylate the TCRζ chain, a component of the TCR complex. Previously, we reported upon the production and characterization of PTPN3-deficient mice which show normal TCR signal transduction and T cell function. To address if the lack of a T cell phenotype in PTPN3-deficient mice can be explained by functional redundancy of PTPN3 with PTPN4, we generated PTPN4-deficient and PTPN4/PTPN3 double-deficient mice. As in PTPN3 mutants, T cell development and homeostasis and TCR-induced cytokine synthesis and proliferation were found to be normal in PTPN4-deficient and PTPN4/PTPN3 double-deficient mice. PTPN13 is another FERM and PDZ domain-containing non-receptor PTP that is distantly-related to PTPN3 and PTPN4 and which has been shown to function as a negative-regulator of T helper-1 (Th1) and Th2 differentiation. Therefore, to determine if PTPN13 might compensate for the loss of PTPN3 and PTPN4 in T cells, we generated mice that lack functional forms of all three PTP. T cells from triple-mutant mice developed normally and showed normal cytokine secretion and proliferative responses to TCR stimulation. Furthermore, T cell differentiation along the Th1, Th2 and Th17 lineages was largely unaffected in triple-mutants. We conclude that PTPN3 and PTPN4 are dispensable for TCR signal transduction

Efficacy of 1998 Vs 2006 first-line antiretroviral regimens for HIV infection: An ordinary clinics retrospective investigation

Purpose: Methods: adhering centers in the Italian CISAI group. Results: For the 543 patients included, mean age was 39.1 ± 9.8y in 1998 and 41.0 ± 10.7y in 2006 (p=0.03), with a similar proportion of males. Baseline mean log10 HIV-RNA was 4.56 ± 0.97 copies/mL in 1998 vs 4.91 ± 0.96 copies/mL in 2006 (p<0.001); baseline mean CD4 T-cell counts were 343 ± 314/mm3 in 1998 vs 244 ± 174/mm3 in HIV-RNA (86.3% vs 58.0%; p<0.001); mean increase in CD4 T-cells count (252 ± 225 vs 173 ± 246; p<0.001); optimal adherence (92.2% vs 82.7%, p=0.03). No differences were observed in the prevalence of grade 3-4 WHO toxicities (26.4% vs 26.6%; p=0.9). Multivariate logistic regression showed that being treated in 1998 remained an independent predictor of virological failure after several adjustments, including adherence. Conclusions: Our data from patients not included in clinical trials or cohort studies provide an additional line of evidenc