SMG1 is a member of the phosphoinositide kinase-like kinase family of proteins that includes ATM, ATR, and DNA-PK, proteins with known roles in DNA damage and cellular stress responses. SMG1 has a well-characterized role in nonsense-mediated decay as well as suggested roles in the DNA damage response, resistance to oxidative stress, regulation of hypoxic responses, and apoptosis. To understand the roles of SMG1 further, we generated a Genetrap Smg1 mouse model. Smg1 homozygous KO mice were early embryonic lethal, but Smg1 heterozygous mice showed a predisposition to a range of cancers, particularly lung and hematopoietic malignancies, as well as development of chronic inflammation. These mice did not display deficiencies in known roles of SMG1, including nonsense-mediated decay. However, they showed elevated basal tissue and serum cytokine levels, indicating low-level inflammation before the development of tumors. Smg1 heterozygous mice also showed evidence of oxidative damage in tissues. These data suggest that the inflammation observed in Smg1 haploinsufficiency contributes to susceptibility to cancer and that Smg1 -deficient animals represent a model of inflammation-enhanced cancer development.

Pathogen-specific polyfunctional T cell responses have been associated with favorable clinical outcomes, but it is not known whether molecular differences exist between polyfunctional and monofunctional cytokine-producing T cells. Here, we report that polyfunctional CD4 ⁺ T cells induced during Plasmodium falciparum ( P . falciparum ) blood-stage infection in humans have a unique transcriptomic profile compared with IFN-γ monofunctional CD4 ⁺ T cells and, thus, are molecularly distinct. The 14-gene signature revealed in P . falciparum –reactive polyfunctional T cells is associated with cytokine signaling and lymphocyte chemotaxis, and systems biology analysis identified IL-27 as an upstream regulator of the polyfunctional gene signature. Importantly, the polyfunctional gene signature is largely conserved in Influenza -reactive polyfunctional CD4 ⁺ T cells, suggesting that polyfunctional T cells have core characteristics independent of pathogen specificity. This study provides the first evidence to our knowledge that consistent molecular differences exist between polyfunctional and monofunctional CD4 ⁺ T cells.

Vaccines are one of the most effective interventions to improve public health, however, the generation of highly effective vaccines for many diseases has remained difficult. Three chronic diseases that characterise these difficulties include malaria, tuberculosis and HIV, and they alone account for half of the global infectious disease burden. The whole organism vaccine approach pioneered by Jenner in 1796 and refined by Pasteur in 1857 with the "isolate, inactivate and inject" paradigm has proved highly successful for many viral and bacterial pathogens causing acute disease but has failed with respect to malaria, tuberculosis and HIV as well as many other diseases. A significant advance of the past decade has been the elucidation of the genomes, proteomes and transcriptomes of many pathogens. This information provides the foundation for new 21st Century approaches to identify target antigens for the development of vaccines, drugs and diagnostic tests. Innovative genome-based vaccine strategies have shown potential for a number of challenging pathogens, including malaria. We advocate that genome-based rational vaccine design will overcome the problem of poorly immunogenic, poorly protective vaccines that has plagued vaccine developers for many years.

Modulation of CD8 coreceptor levels can profoundly affect T-cell sensitivity to antigen. Here we show that the heritable downregulation of CD8 during type 2 polarization of murine CD8(+) effector T cells in vitro and in vivo is associated with CpG methylation of several regions of the Cd8a locus. These epigenetic modifications are maintained long-term in vivo following adoptive transfer. Even after extended type 2 polarization, however, some CD8(low) effector cells respond to interferon-γ by re-expressing CD8 and a type 1 cytokine profile in association with partial Cd8a demethylation. Cd8a methylation signatures in naive, polarized and repolarized cells are distinct from those observed during the initiation, maintenance and silencing of CD8 expression by developing T cells in the thymus. This persistent capacity for epigenetic reprogramming of coreceptor levels on effector CD8(+) T cells enables the heritable tuning of antigen sensitivity in parallel with changes in type 1/type 2 cytokine balance.

The CD8 co-receptor can modulate CD8⁺ T cell function through its contributions to T cell receptor (TCR) binding and signaling. Here we show that IFN-γ and IL-4 exert opposing effects on the expression of CD8α mRNA and surface CD8 protein during CD8⁺ T cell activation. IL-4 caused down-regulation of surface CD8 on ovalbumin (OVA)_257–264-specific TCR-transgenic OT-I CD8⁺ T cells activated with OVA_257–264-coated antigen presenting cells or polyclonal stimuli, and on wild type CD8⁺ T cells activated with polyclonal stimuli. This effect was enhanced in each case when the cells lacked a functional IFN-γ or IFN-γR gene. When WT or IFN-γ-deficient OT-I CD8⁺ T cells were analyzed 9 days after co-injection with control or IL-4-expressing OVA⁺ tumor cells into RAG-2^−/−γc^−/− mice, CD8 levels were highest on WT donor cells from mice that received the control tumor and lowest on IFN-γ-deficient donor cells from mice that received the IL-4-expressing tumor. The latter CD8^low cells displayed markedly impaired binding of OVA_257–264/MHC tetramers and peptide/MHC-dependent degranulation. The data reveal an unexpected role for IFN-γ in tuning the CD8 co-receptor during primary CD8⁺ T cell activation both in vitro and in vivo.

Using a unique resource of samples from a controlled human malaria infection (CHMI) study, we identified a novel population of CD4⁺ T cells whose frequency in the peripheral blood was inversely correlated with parasite burden following P. falciparum infection. These CD4⁺ T cells expressed the multifunctional ectoenzyme CD38 and had unique features that distinguished them from other CD4⁺ T cells. Specifically, their phenotype was associated with proliferation, activation and cytotoxic potential as well as significantly impaired production of IFN-γ and other cytokines and reduced basal levels of activated STAT1. A CD38⁺ CD4⁺ T cell population with similar features was identified in healthy uninfected individuals, at lower frequency. CD38⁺ CD4⁺ T cells could be generated in vitro from CD38^- CD4⁺ T cells after antigenic or mitogenic stimulation. This is the first report of a population of CD38⁺ CD4⁺ T cells with a cytotoxic phenotype and markedly impaired IFN-γ capacity in humans. The expansion of this CD38⁺ CD4⁺ T population following infection and its significant association with reduced blood-stage parasite burden is consistent with an important functional role for these cells in protective immunity to malaria in humans. Their ubiquitous presence in humans suggests that they may have a broad role in host-pathogen defense. ClinicalTrials.gov clinical trial numbers ACTRN12612000814875, ACTRN12613000565741 and ACTRN12613001040752 Malaria is one of the three most deadly infectious disease worldwide, together with tuberculosis and HIV. The exact mechanisms underlying effective immunity to malaria remain largely unknown and there is no reliable immune correlate of protection. Here, we take advantage of a unique experimental human infection model to define the immune response to primary exposure of blood-stage malaria parasites in naïve healthy volunteers at the molecular level. We report that Plasmodium parasite levels were inversely correlated to the expansion of a specific subset of CD4⁺ T cells expressing the activation molecule CD38 and a very unusual phenotype. Although the expansion of CD38⁺ CD4⁺ T cells has been described in several viral and bacterial infections, we show for the first time that these cells are associated with a ‘naive-like’ effector phenotype, higher cytolytic potential and a strongly impaired ability to produce IFN-γ and other cytokines. Importantly, this subset of CD38⁺ CD4⁺ T cells could be also identified in all healthy volunteers prior to infection, suggesting that these core characteristics of circulating CD38⁺ CD4⁺ T cells are independent of active infection and may play an important role in the immune control of other pathogens.