Regulation of human CD4+ T cell differentiation

Naive CD4+ T cells differentiate into specific effector subsets—Th1, Th2, Th17, and T follicular helper (Tfh)—that provide immunity against pathogen infection. The signaling pathways involved in generating these effector cells are partially known. However, the effects of mutations underlying human primary immunodeficiencies on these processes, and how they compromise specific immune responses, remain unresolved. By studying individuals with mutations in key signaling pathways, we identified nonredundant pathways regulating human CD4+ T cell differentiation in vitro. IL12Rβ1/TYK2 and IFN-γR/STAT1 function in a feed-forward loop to induce Th1 cells, whereas IL-21/IL-21R/STAT3 signaling is required for Th17, Tfh, and IL-10–secreting cells. IL12Rβ1/TYK2 and NEMO are also required for Th17 induction. Strikingly, gain-of-function STAT1 mutations recapitulated the impact of dominant-negative STAT3 mutations on Tfh and Th17 cells, revealing a putative inhibitory effect of hypermorphic STAT1 over STAT3. These findings provide mechanistic insight into the requirements for human T cell effector function, and explain clinical manifestations of these immunodeficient conditions. Furthermore, they identify molecules that could be targeted to modulate CD4+ T cell effector function in the settings of infection, vaccination, or immune dysregulation

Evidence of a Generalized Defect of Acinar Cell Function in Shwachman-Diamond Syndrome

: Because the acinar cells of the exocrine pancreas in patients with Shwachman-Diamond syndrome (SDS) are severely depleted, we hypothesized that a similar deficiency may be present in acinar cells of the parotid gland

Chronic hepatitis B and C infection in children in New South Wales

Objective: To characterise epidemiological, clinical and laboratory features of children in New South Wales with chronic hepatitis B (HBV) or C (HCV) infections. Design and setting: Retrospective record review of epidemiological, clinical, laboratory, liver biopsy and treatment data for children (aged < 18 years) referred to tertiary referral paediatric and refugee clinics in NSW with chronic HBV or HCV during 2000–2007; and comparison with NSW Health notification data for the same period. Main outcome measures: Numbers and characteristics of referred children with HBV and HCV, and notifications to NSW Health. Results: During 2000–2007, 79 children with chronic HBV and 29 with HCV infection were referred to specialist clinics, while 930 children with HBV and 777 with HCV infection were reported to NSW Health. Most of the referred children with HBV were born overseas, while most with HCV were born in Australia to mothers with a history of intravenous drug use. Of the 79 HBV-infected children, 56 were e-antigen positive. Most HCV-infected children (23/29) had alanine aminotransferase levels ≤ 2 times the upper limit of normal, and more than half of those who had genotype determined had type 2 or 3. Fibrosis was evident in liver biopsies performed for both HBV and HCV. Conclusions: Although advanced liver disease was uncommon in children referred with HBV or HCV infection, a large number of infected children in NSW were not referred for specialist medical care, indicating that opportunities to intervene early in the natural history of these infections, particularly HCV, are being missed

Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4⁺ T cells into distinct effector subsets

Naive CD4(+) T cells differentiate into specific effector subsets—Th1, Th2, Th17, and T follicular helper (Tfh)—that provide immunity against pathogen infection. The signaling pathways involved in generating these effector cells are partially known. However, the effects of mutations underlying human primary immunodeficiencies on these processes, and how they compromise specific immune responses, remain unresolved. By studying individuals with mutations in key signaling pathways, we identified nonredundant pathways regulating human CD4(+) T cell differentiation in vitro. IL12Rβ1/TYK2 and IFN-γR/STAT1 function in a feed-forward loop to induce Th1 cells, whereas IL-21/IL-21R/STAT3 signaling is required for Th17, Tfh, and IL-10–secreting cells. IL12Rβ1/TYK2 and NEMO are also required for Th17 induction. Strikingly, gain-of-function STAT1 mutations recapitulated the impact of dominant-negative STAT3 mutations on Tfh and Th17 cells, revealing a putative inhibitory effect of hypermorphic STAT1 over STAT3. These findings provide mechanistic insight into the requirements for human T cell effector function, and explain clinical manifestations of these immunodeficient conditions. Furthermore, they identify molecules that could be targeted to modulate CD4(+) T cell effector function in the settings of infection, vaccination, or immune dysregulation