Activated human T cells express HLA-DR, HLA-DQ, and HLA-DP on their surface, but the regulation and functioning of MHC class II molecules in T lymphocytes are poorly understood. Because the MHC class II transactivator (CIITA) is essential for MHC class II expression, we have investigated transcriptional activation of CIITA in activated T cells. In this study, we show that in human activated CD4+ T cells, CIITA promoter III (CIITA-PIII) drives the expression of CIITA. The in vivo genomic footprint analysis revealed activated T cell-specific occupation of CIITA-PIII. Subsequent EMSA analysis of several promoter regions showed differences in banding pattern among activated T cells, naive T cells, primary B cells, and Raji B cells. Activating response element (ARE)-1 is shown to interact with the acute myeloid leukemia 2 transcription factor in nuclear extracts derived from both T and B cells. Interestingly, the acute myeloid leukemia 3 transcription factor was bound in nuclear extracts of T cells only. The ARE-2 sequence is able to bind CREB/activating transcription factor family members in both T and B cells. In addition, a yet unidentified Ets family member was found to interact with site C in activated T cells, whereas in B cells site C was bound by PU.1 and Pip/IFN regulatory factor 4/IFN consensus sequence binding protein for activated T cells. In Jurkat T cells, both ARE-1 and ARE-2 are crucial for CIITA-PIII activity, similar to Raji B cells. The differential banding pattern in in vivo genomic footprinting and transcription factor binding at the ARE-1 and site C between T cells and B cells probably reflects differences in CIITA-PIII activation pathways employed by these cell types.

Identifying molecular predictors and mechanisms of malaria disease is important for understanding how Plasmodium falciparum malaria is controlled. Transcriptomic studies in humans have so far been limited to retrospective analysis of blood samples from clinical cases. In this prospective, proof-of-principle study, we compared whole-blood RNA-seq profiles at pre-and post-infection time points from Malian adults who were either asymptomatic (n = 5) or febrile (n = 3) during their first seasonal PCR-positive P. falciparum infection with those from malaria-naïve Dutch adults after a single controlled human malaria infection (n = 5). Our data show a graded activation of pathways downstream of pro-inflammatory cytokines, with the highest activation in malaria-naïve Dutch individuals and significantly reduced activation in malaria-experienced Malians. Newly febrile and asymptomatic infections in Malians were statistically indistinguishable except for genes activated by pro-inflammatory cytokines. The combined data provide a molecular basis for the development of a pyrogenic threshold as individuals acquire immunity to clinical malaria.

Cytotoxic T-lymphocytes play an important role in the protection against viral infections, which they detect through the recognition of virus-derived peptides, presented in the context of MHC class I molecules at the surface of the infected cell. The transporter associated with antigen processing (TAP) plays an essential role in MHC class I–restricted antigen presentation, as TAP imports peptides into the ER, where peptide loading of MHC class I molecules takes place. In this study, the UL49.5 proteins of the varicelloviruses bovine herpesvirus 1 (BHV-1), pseudorabies virus (PRV), and equine herpesvirus 1 and 4 (EHV-1 and EHV-4) are characterized as members of a novel class of viral immune evasion proteins. These UL49.5 proteins interfere with MHC class I antigen presentation by blocking the supply of antigenic peptides through inhibition of TAP. BHV-1, PRV, and EHV-1 recombinant viruses lacking UL49.5 no longer interfere with peptide transport. Combined with the observation that the individually expressed UL49.5 proteins block TAP as well, these data indicate that UL49.5 is the viral factor that is both necessary and sufficient to abolish TAP function during productive infection by these viruses. The mechanisms through which the UL49.5 proteins of BHV-1, PRV, EHV-1, and EHV-4 block TAP exhibit surprising diversity. BHV-1 UL49.5 targets TAP for proteasomal degradation, whereas EHV-1 and EHV-4 UL49.5 interfere with the binding of ATP to TAP. In contrast, TAP stability and ATP recruitment are not affected by PRV UL49.5, although it has the capacity to arrest the peptide transporter in a translocation-incompetent state, a property shared with the BHV-1 and EHV-1 UL49.5. Taken together, these results classify the UL49.5 gene products of BHV-1, PRV, EHV-1, and EHV-4 as members of a novel family of viral immune evasion proteins, inhibiting TAP through a variety of mechanisms.

These data show that increased inflammation, vasculoneogenesis and cytotoxicity, perturbed T-cell regulation as well as IFN-induced genes play an important role in T1R and provide potential T1R-specific host biomarkers.

The class II transactivator (CIITA) plays a pivotal role in the expression of major histocompatibility complex (MHC) class II and accessory genes (invariant chain [Ii] and HLA-DM), whereas it has an ancillary function in the expression of MHC class I and ␤ 2 -microglobulin (␤ 2 m) genes. 1-9 The MHC is a large multigene family that encodes cell surface glycoproteins involved in binding and presentation of antigenic peptides to T lymphocytes. The products of the ␤ 2 m, Ii and HLA-DM genes are also essential proteins in MHC class I-and class II-mediated antigen presentation function, respectively. For this reason CIITA-mediated MHC expression is central in the generation of an antigen-specific immune response by presenting antigenic peptides to the T-cell receptor (TCR) on T lymphocytes. 10,11 MHC class I molecules are expressed on almost all nucleated cells. In contrast, the constitutive expression of MHC class II molecules is restricted to specific immune cell types that include antigen-presenting cells such as dendritic cells, B lymphocytes, macrophages and thymic epithelial cells. Nonimmune cells lack constitutive expression of MHC class II; however, in most of these cells MHC class II expression can be induced by interferon-␥ (IFN-␥). 12,13 Notably, expression of MHC class I molecules can also be enhanced by IFN-␥. Together, the upregulated expression of MHC class I and class II molecules results in an increase in the immunogenic potential of cells. The importance of MHC expression by tumor cells in mounting an effective antitumor immune response has been shown in animal models for T-cell-mediated immunotherapy 14 -16 and is corroborated by the notion that tumors expressing high levels of both MHC class I and class II molecules display abundant lymphocytic infiltration. [17][18][19] Notably, patients with high tumorlytic lymphocyte infiltrates generally have a better prognosis. [17][18][19] Several tissues have been shown to exhibit a significantly reduced membrane expression of MHC class I molecules. In particular, certain reproductive and developmental tissues lack expression of MHC class I molecules, including sperm, 20 oocytes, 21 preimplantation embryos 22 and villous trophoblast cells. 23 The absence of MHC molecules from fetal and embryonic tissues creates an immune privilege for these cells during gestation and may be of functional significance during development. Also, several malignant cell types have been shown to lack the expression of MHC molecules. This reduced expression of MHC molecules will contribute to a decreased recognition by T cells, allowing an escape from immunosurveillance. 24 -26 Interestingly, most of the MHC-deficient tumor cells have originated from fetal or embryonic tissues. Downregulation of MHC gene expression in these embryonic or developmental tumors may therefore not result from the neoplastic transformation event but may instead reflect the characteristic silent state of MHC class I and class II genes during early development.To understand the mechanisms of downregulat...