It may seem counterintuitive that

It may seem counterintuitive that a lymphocyte which is unable to proliferate could have neoplastic potential since the very definition of neoplasia is one of autonomous clonal expansion of a cell. The lack of co-stimulatory molecules CD27 and CD28 can potentially be overcome by activating NK cell receptors such as NKG2D with its specific ligand, defining a venue for proliferation in a cell that is otherwise not designed for cellular propagation [16]. Another potential manner in which T cell proliferation can occur is one of interleukin (IL)-15 release from the monocytes. CD4+ CD28null T vorinostat do not proliferate in response to allogeneic stimulation, unless IL-15 is added. However, the additional IL-15 increases the frequency of proliferating alloreactive T cells to 30.5% without inducing CD28 expression [17]. As a point of reiteration, the literature precedent on CD4 + T cell lymphomas of the skin exhibiting cytotoxic properties is limited to endogenous CD30 positive LPDs represented by ALCL, LyP and tumor stage MF with large cell transformation. When one considers cytotoxic granule expression in the benign lymphocyte counterpart, the classic cell types are natural killer cells, double negative gamma delta T cells and cytotoxic CD8 positive T cells. The cytotoxic molecules include the specific proteases granzyme A and B and T cell restricted intracellular antigen. Each of the cytotoxic proteins plays an important role leading to cell death. Perforin for example elicits disruption of the integrity of the cytoplasmic membrane while granzyme results in the initiation of cellular apoptosis through the activation of caspases. The critical role of these cytotoxic granules is in the context of immunosurveillance killing of tumor cells and exogenous pathogens [15,18]. The delivery of cytotoxic proteins to target cells enables neoplastic cells to induce apoptosis/cell death of critical immunosurveillance anti-tumor cells, hence facilitating tumor progression. Paradoxically, lymphocytes that express these cytotoxic proteins do not specifically undergo apoptosis due to various protective mechanisms including intracytoplasmic inhibitors of serine proteases namely serpins and a cell surface protective molecule that prevents the disruption of the cytoplasmic membrane by perforins [15].
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Introduction Flaviviruses are typically transmitted to humans by infected mosquitoes or ticks. The most important human-pathogenic representatives are yellow fever (YF), Japanese encephalitis (JE), West Nile (WN), dengue (DEN), Zika and tick-borne encephalitis (TBE) viruses, which constitute significant health problems in many parts of the world. The expansion of flavivirus endemic areas and their ability to cause epidemics are most dramatically exemplified by the expansion of DEN hyperendemic areas [1], the expansion of WN virus in the Americas after its introduction to New York in 1999 [2] and its emergence in a number of countries of Southern Europe [3], the recent Zika epidemic in the South Pacific and the Americas [4], and the detection of new infection sites of TBE virus in certain parts of Europe (reviewed in [5,6]). It has been estimated that over half of the global population is at risk for infection with one of the four DEN virus serotypes, and YF, DEN, JE, and WN viruses collectively cause millions of infections and tens of thousands of deaths each year [7,8]. Despite this significant disease burden, vaccines exist for only a few flaviviruses (YF, TBE and JE viruses) [9]. The development of a DEN vaccine is especially challenging due to the need to simultaneously induce protection against all four serotypes and the concern that vaccination could predispose to severe disease with low levels of antibody giving rise to enhancement of subsequent infection [10]. Although significant progress has been made with the licensing of the first tetravalent DEN vaccine (Dengvaxia®) [11], the recent results of large scale efficacy trials, which revealed only 30–65% protection despite detectable neutralizing antibodies in vitro [[12], [13], [14]], emphasize the critical need to better understand the immune processes underlying protective immunity.