Transcriptional reprogramming of mature CD4⁺ helper T cells generates distinct MHC class II-restricted cytotoxic T lymphocytes.

TCRαß thymocytes differentiate into either CD8αß(+) cytotoxic T lymphocytes or CD4(+) helper T cells. This functional dichotomy is controlled by key transcription factors, including the helper T cell master regulator ThPOK, which suppresses the cytolytic program in major histocompatibility complex (MHC) class II-restricted CD4(+) thymocytes. ThPOK continues to repress genes of the CD8 lineage in mature CD4(+) T cells, even as they differentiate into effector helper T cell subsets. Here we found that the helper T cell fate was not fixed and that mature, antigen-stimulated CD4(+) T cells terminated expression of the gene encoding ThPOK and reactivated genes of the CD8 lineage. This unexpected plasticity resulted in the post-thymic termination of the helper T cell program and the functional differentiation of distinct MHC class II-restricted CD4(+) cytotoxic T lymphocytes.

CD4 CTL: living up to the challenge.

During thymic development, thymocytes expressing a T cell receptor consisting of an alpha and beta chain (TCRαß), commit to either the cytotoxic- or T helper-lineage fate. This lineage dichotomy is controlled by key transcription factors, including the T helper (Th) lineage master regulator, the Th-inducing BTB/POZ domain-containing Kruppel-like zinc-finger transcription factor, ThPOK, (formally cKrox or Zfp67; encoded by Zbtb7b), which suppresses the cytolytic program in major histocompatibility complex (MHC) class II-restricted CD4(+) thymocytes and the Runt related transcription factor 3 (Runx3), which counteracts ThPOK in MHC class I restricted precursor cells and promotes the lineage commitment of CD8αß(+) cytolytic T lymphocytes (CTL). ThPOK continues to repress the CTL gene program in mature CD4(+) T cells, even as they differentiate into effector Th cell subsets. The Th cell fate however is not fixed and two recent studies showed that mature, antigen-stimulated CD4(+) T cells have the flexibility to terminate the expression of ThPOK and functionally reprogram to cytotoxic effector cells. This unexpected plasticity of CD4(+) T cells results in the post-thymic termination of the Th lineage fate and the functional differentiation of distinct MHC class II-restricted CD4(+) CTL. The recognition of CD4 CTL as a defined separate subset of effector cells and the identification of the mechanisms and factors that drive their reprogramming finally create new opportunities to explore the physiological relevance of these effector cells in vivo and to determine their pivotal roles in both, protective immunity as well as in immune-related pathology.

Evidence of hepatitis E virus exposure among seronegative healthy residents of an endemic area.

OBJECTIVE: Hepatitis E virus (HEV) infection is endemic in the Indian subcontinent. Detection of serum anti-HEV IgG has traditionally been used to determine prior exposure to this virus. We studied HEV-specific recall immune responses in healthy subjects with and without detectable anti-HEV IgG. METHODS: Memory B and T cells specific for HEV recombinant proteins pORF2 and pORF3 were estimated among healthy subjects residing in an HEV-endemic region using enzyme-linked immunospot (ELISPOT) assays. RESULTS: Anti-HEV IgG-negative and anti-HEV IgG-positive healthy subjects had a similar median (range) number of IgG-secreting memory B cells specific for HEV pORF2 [percent of total IgG-producing cells: 0.39 (0-13.63) vs. 0.83 (0-12.78)] and HEV pORF3 [0.33 (0.05-12.35) vs. 1.01 (0.08-9.48)], and of IFN-γ-secreting memory T cells specific for HEV pORF2 [per one million PBMCs: 16 (0-220) vs. 36.5 (0-474)] and HEV pORF3 [166 (0-957) vs. 70.5 (0-533)]. Eight healthy volunteers residing in the USA and studied as controls lacked detectable T cells specific for HEV pORF2. CONCLUSION: ELISPOT assays may detect evidence of prior HEV infection in persons residing in areas endemic for this infection and lacking detectable anti-HEV IgG. Seroepidemiological studies that use the serum anti-HEV IgG test may underestimate the frequency of exposure to HEV.