Top Reads

In this Top Read, Gillig et al. (p. 1783) identified and characterized a colon carcinoma neoepitope, junction plakoglobin mutant (Jup^MUT) protein. The authors purified MHC-bound epitopes and used mass spectrometry to identify Jup^MUT. Modeling of the sequenced epitope and its wild-type (WT) correlate predicted similar conformational binding to H-2D^b, but H-2K^b models resulted in different conformational binding, with Jup^MUT displaying a hydrophobic side chain, which has been previously correlated with neoepitope immunogenicity. Prophylactic immunization with Jup^MUT, but not Jup^WT, significantly restricted tumor growth in mice. The protective effect of Jup^MUT was lost when CD8 T cells were deleted, suggesting that CD8 T cells are necessary for Jup^MUT-mediated tumor rejection. However, Jup^MUT-specific CD8 T cells showed no production of either IFN-γ or TNF-α when examined ex vivo. Additionally, the authors were unable to expand Jup^MUT-specific CD8 T cells in vitro. These data provide both an exciting potential neoepitope for cancer therapy and a mystery that requires further investigation into how CD8 T cells contribute to the antitumor response.

In this Top Read, Helms et al. (p. 1767) sought to evaluate the role of PAS domain-containing serine/threonine kinase (PASK)/WD repeat domain 5 (WDR5) pathway in regulating T cell differentiation and acquisition of effector function. Activation and expansion of CD8⁺ T cells in the presence of BioE-1197, a novel PASK inhibitor, stably enhanced effector cytokine production. However, this effect was independent of PASK as PASK-deficient CD8⁺ T cells demonstrated cytokine production levels, similar to WT cells in the presence of BioE-1197. Subsequent basic local alignment search tool analysis revealed members of the AMP-activated protein kinase (AMPK) related kinases (ARK) family as potential targets of BioE-1197. Consistent with this, treatment of CD8⁺ T cells deficient in liver kinase B1 (LKB1) with BioE-1197 revealed that LKB1-mediated activation of salt-inducible kinases (SIK) epigenetically regulated cytokine recall potential in effector CD8⁺ and Th1 cells. Subsequent analysis revealed that this phenotype was due to SIK-mediated phosphorylation-dependent stabilization of histone deacetylase 7 (HDAC7) during late-stage effector differentiation, specifically via loci-specific reduction in the activation transcription mark, histone 3 lysine 27 acetylation (H3K27Ac). Thus, this work identifies a novel pathway capable of regulating effector cytokine functionality in CD8⁺ T and Th1 cells, suggesting that targeted interruption of SIK activity may be a potential therapeutic target for enhancing T cell functionality.

Using mouse strains designed with deletions in either the TRAF2/3 or TRAF6 binding domain of CD40, in this Top Read, Lu et al. (p. 1814) elucidated the role of these functional motifs in the pathology of experimental autoimmune encephalitis (EAE). Compared to wild-type (WT) mice, all TRAF mutants showed reduced EAE severity. However, chimeric mice with B cell–specific TRAF mutations developed EAE comparable to the WT mice. Additionally, induction of EAE with a B cell–independent Ag resulted in reduced EAE pathology in all TRAF mutant mice, suggesting that EAE pathology is dependent on TRAF binding in non–B cell APCs. Both TRAF2/3 and TRAF 6 motifs have a role in the T cell response as evidenced by a decrease of CD4 T cells and a decrease in the frequency of pathogenic Th17 T cells in the draining lymph nodes and CNS of TRAF mutant mice. However, only mice with deletions in TRAF2/3, but not TRAF 6, showed a reduced number of B cells in germinal centers and lower levels of high-affinity IgG. Together, these data show that CD40 binding motifs on two different TRAF proteins have distinct roles in the pathology of EAE.