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1. A split, conditionally active mimetic of IL-2 reduces the toxicity of systemic cytokine therapy

   https://doi.org/10.1038/s41587-022-01510-z  

   Quijano-Rubio, Alfredo ; Bhuiyan, Aladdin M. ; Yang, Huilin ; Leung, Isabel ; Bello, Elisa ; Ali, Lestat R. ; Zhangxu, Kevin ; Perkins, Jilliane ; Chun, Jung-Ho ; Wang, Wentao ; et al ( October 2022 , Nature Biotechnology)

   The therapeutic potential of recombinant cytokines has been limited by the severe side effects of systemic administration. We describe a strategy to reduce the dose-limiting toxicities of monomeric cytokines by designing two components that require colocalization for activity and that can be independently targeted to restrict activity to cells expressing two surface markers. We demonstrate the approach with a previously designed mimetic of cytokines interleukin-2 and interleukin-15—Neoleukin-2/15 (Neo-2/15)—both fortrans-activating immune cells surrounding targeted tumor cells and forcis-activating directly targeted immune cells. Intrans-activation mode, tumor antigen targeting of the two components enhanced antitumor activity and attenuated toxicity compared with systemic treatment in syngeneic mouse melanoma models. Incis-activation mode, immune cell targeting of the two components selectively expanded CD8⁺ T cells in a syngeneic mouse melanoma model and promoted chimeric antigen receptor T cell activation in a lymphoma xenograft model, enhancing antitumor efficacy in both cases.

    

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2. Trib1 regulates T cell differentiation during chronic infection by restraining the effector program

   https://doi.org/10.1084/jem.20190888  

   Rome, Kelly S. ; Stein, Sarah J. ; Kurachi, Makoto ; Petrovic, Jelena ; Schwartz, Gregory W. ; Mack, Ethan A. ; Uljon, Sacha ; Wu, Winona W. ; DeHart, Anne G. ; McClory, Susan E. ; et al ( March 2020 , Journal of Experimental Medicine)

   In chronic infections, the immune response fails to control virus, leading to persistent antigen stimulation and the progressive development of T cell exhaustion. T cell effector differentiation is poorly understood in the context of exhaustion, but targeting effector programs may provide new strategies for reinvigorating T cell function. We identified Tribbles pseudokinase 1 (Trib1) as a central regulator of antiviral T cell immunity, where loss of Trib1 led to a sustained enrichment of effector-like KLRG1+ T cells, enhanced function, and improved viral control. Single-cell profiling revealed that Trib1 restrains a population of KLRG1+ effector CD8 T cells that is transcriptionally distinct from exhausted cells. Mechanistically, we identified an interaction between Trib1 and the T cell receptor (TCR) signaling activator, MALT1, which disrupted MALT1 signaling complexes. These data identify Trib1 as a negative regulator of TCR signaling and downstream function, and reveal a link between Trib1 and effector versus exhausted T cell differentiation that can be targeted to improve antiviral immunity.

    

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3. Transcriptional and epigenetic regulators of human CD8+ T cell function identified through orthogonal CRISPR screens

   https://doi.org/10.1038/s41588-023-01554-0  

   McCutcheon, Sean R. ; Swartz, Adam M. ; Brown, Michael C. ; Barrera, Alejandro ; McRoberts Amador, Christian ; Siklenka, Keith ; Humayun, Lucas ; ter Weele, Maria A. ; Isaacs, James M. ; Reddy, Timothy E. ; et al ( November 2023 , Nature Genetics)

   Clinical response to adoptive T cell therapies is associated with the transcriptional and epigenetic state of the cell product. Thus, discovery of regulators of T cell gene networks and their corresponding phenotypes has potential to improve T cell therapies. Here we developed pooled, epigenetic CRISPR screening approaches to systematically profile the effects of activating or repressing 120 transcriptional and epigenetic regulators on human CD8⁺T cell state. We found that BATF3 overexpression promoted specific features of memory T cells and attenuated gene programs associated with cytotoxicity, regulatory T cell function, and exhaustion. Upon chronic antigen stimulation, BATF3 overexpression countered phenotypic and epigenetic signatures of T cell exhaustion. Moreover, BATF3 enhanced the potency of CAR T cells in both in vitro and in vivo tumor models and programmed a transcriptional profile that correlates with positive clinical response to adoptive T cell therapy. Finally, we performed CRISPR knockout screens that defined cofactors and downstream mediators of the BATF3 gene network.

    

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4. Magnitude and breadth of antibody cross-reactivity induced by recombinant influenza hemagglutinin trimer vaccine is enhanced by combination adjuvants

   https://doi.org/10.1038/s41598-022-12727-y  

   Hernandez-Davies, Jenny E. ; Dollinger, Emmanuel P. ; Pone, Egest J. ; Felgner, Jiin ; Liang, Li ; Strohmeier, Shirin ; Jan, Sharon ; Albin, Tyler J. ; Jain, Aarti ; Nakajima, Rie ; et al ( June 2022 , Scientific Reports)

   The effects of adjuvants for increasing the immunogenicity of influenza vaccines are well known. However, the effect of adjuvants on increasing the breadth of cross-reactivity is less well understood. In this study we have performed a systematic screen of different toll-like receptor (TLR) agonists, with and without a squalene-in-water emulsion on the immunogenicity of a recombinant trimerized hemagglutinin (HA) vaccine in mice after single-dose administration. Antibody (Ab) cross-reactivity for other variants within and outside the immunizing subtype (homosubtypic and heterosubtypic cross-reactivity, respectively) was assessed using a protein microarray approach. Most adjuvants induced broad IgG profiles, although the response to a combination of CpG, MPLA and AddaVax (termed ‘IVAX-1’) appeared more quickly and reached a greater magnitude than the other formulations tested. Antigen-specific plasma cell labeling experiments show the components of IVAX-1 are synergistic. This adjuvant preferentially stimulates CD4 T cells to produce Th1>Th2 type (IgG2c>IgG1) antibodies and cytokine responses. Moreover, IVAX-1 induces identical homo- and heterosubtypic IgG and IgA cross-reactivity profiles when administered intranasally. Consistent with these observations, a single-cell transcriptomics analysis demonstrated significant increases in expression of IgG1, IgG2b and IgG2c genes of B cells in H5/IVAX-1 immunized mice relative to naïve mice, as well as significant increases in expression of the IFNγ gene of both CD4 and CD8 T cells. These data support the use of adjuvants for enhancing the breath and durability of antibody responses of influenza virus vaccines.

    

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5. IL-10 producing CD8+ CD122+ PD-1+ regulatory T cells are expanded by dendritic cells silenced for Allograft Inflammatory Factor-1

   https://doi.org/10.1002/JLB.1A0118-010RR  

   Elizondo, Diana M. ; Andargie, Temesgen E. ; Haddock, Naomi L. ; da Silva, Ricardo L. Louzada ; de Moura, Tatiana Rodrigues ; Lipscomb, Michael W. ( December 2018 , Journal of Leukocyte Biology)

   Allograft Inflammatory Factor-1 (AIF1) is a cytoplasmic scaffold protein that contains Ca2+ binding EF-hand and PDZ interaction domains important for mediating intracellular signaling complexes in immune cells. The protein plays a dominant role in both macrophage- and dendritic cell (DC)-mediated inflammatory responses. This study now reports that AIF1 expression in DC is important in directing CD8+ T cell effector responses. Silencing AIF1 expression in murine CD11c+ DC suppressed antigen-specific CD8+ T cell activation, marked by reduced CXCR3, IFNγ and Granzyme B expression, and restrained proliferation. These primed CD8+ T cells had impaired cytotoxic killing of target cells in vitro. In turn, studies identified that AIF1 silencing in DC robustly expanded IL-10 producing CD8+ CD122+ PD-1+ regulatory T cells that suppressed neighboring immune effector responses through both IL-10 and PD-1-dependent mechanisms. In vivo studies recapitulated bystander suppression of antigen-responsive CD4+ T cells by the CD8+ Tregs expanded from the AIF1 silenced DC. These studies further demonstrate that AIF1 expression in DC serves as a potent governor of cognate T cell responses and present a novel target for engineering tolerogenic DC-based immunotherapies.

   Adaptive immune responses are impaired in CD8+ T cells primed by DC silenced for AIF1.

    

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