Significance The protooncogene c-Myc (Myc) is an oncogenic driver in many cancers, but is difficult to target directly with drugs. An alternative strategy is to use drugs that inhibit factors that regulate Myc expression. Notch drives Myc expression in most T-cell leukemias, but clinical trials of Notch inhibitors have been disappointing, possibly because cells emerge that express Myc in a Notch-independent fashion. Here we identify the genomic switches that regulate Myc expression in the Notch-inhibitor–sensitive and –resistant states. Our findings suggest that Notch inhibitor resistance occurs through a “switch swap” that relieves Notch dependency while increasing dependency on a different factor, bromodomain containing 4 (Brd4). These studies provide a rationale for targeting Myc in T cell leukemias with combinations of Notch and Brd4 inhibitors.

Activation of CD4+ T cells through interactions with peptides bound to Major Histocompatibility Complex Class II (MHC-II) molecules is a crucial step in clearance of most pathogens. Consequently, many viruses have evolved ways of blocking this aspect of adaptive immunity, from specific targeting of processing and presentation components to modulation of signaling pathways that regulate peptide presentation in addition to many other host defense mechanisms. Such cases of interference are far less common compared to what has been elucidated in MHC-I processing and presentation. This may be attributable in part to the complexity of MHC-II antigen processing, the scope of which is only now coming to light.

Females have more robust immune responses than males, and viral infections are more severe for males. Hormones and genetic sex, namely the X chromosome, influence sex differences with immune responses. Here, we review recent findings underlying sexual dimorphism of disease susceptibility for two prevalent viral infections, influenza and SARS-CoV-2, which exhibit male-biased disease severity. Viral infections are proposed to be an initiating event for autoimmunity, which exhibits a female bias. We also review recent work elucidating the epigenetic and genetic contribution of X-Chromosome Inactivation maintenance, and X-linked gene expression, for the autoimmune disorder Systemic Lupus Erythematosus, and highlight the complex considerations required for identifying underlying hormonal and genetic contributions responsible for sex differences in immune responses.

Smallpox and monkeypox pose severe threats to human health. Other orthopoxviruses are comparably virulent in their natural hosts, including ectromelia, the cause of mousepox. Disease severity is linked to an array of immunomodulatory proteins including the B22 family, which has homologs in all pathogenic orthopoxviruses but not attenuated vaccine strains. We demonstrate that the ectromelia B22 member, C15, is necessary and sufficient for selective inhibition of CD4 + but not CD8 + T cell activation by immunogenic peptide and superantigen. Inhibition is achieved not by down-regulation of surface MHC- II or co-stimulatory protein surface expression but rather by interference with antigen presentation. The appreciable outcome is interference with CD4 + T cell synapse formation as determined by imaging studies and lipid raft disruption. Consequently, CD4 + T cell activating stimulus shifts to uninfected antigen-presenting cells that have received antigen from infected cells. This work provides insight into the immunomodulatory strategies of orthopoxviruses by elucidating a mechanism for specific targeting of CD4 + T cell activation, reflecting the importance of this cell type in control of the virus.

CD4+ T cells play critical roles in defending against poxviruses, both by potentiating cellular and humoral responses and by directly killing infected cells. Despite this central role, the basis for pox-specific CD4+ T cell activation, specifically the origin of the poxvirus-derived peptides (epitopes) that activate CD4+ T cells, remains poorly understood. In addition, because the current licensed poxvirus vaccines can cause serious adverse events and even death, elucidating the requirements for MHC class II (MHC-II) processing and presentation of poxviral Ags could be of great use. To address these questions, we explored the CD4+ T cell immunogenicity of ectromelia, the causative agent of mousepox. Having identified a large panel of novel epitopes via a screen of algorithm-selected synthetic peptides, we observed that immunization of mice with inactivated poxvirus primes a virtually undetectable CD4+ T cell response, even when adjuvanted, and is unable to provide protection against disease after a secondary challenge. We postulated that an important contributor to this outcome is the poor processability of whole virions for MHC-II–restricted presentation. In line with this hypothesis, we observed that whole poxvirions are very inefficiently converted into MHC-II–binding peptides by the APC as compared with subviral material. Thus, stability of the virion structure is a critical consideration in the rational design of a safe alternative to the existing live smallpox vaccine.