Anand Balasubramani

Fueling T cell proliferation

Thymus Previous studies on BRCA1-associated protein-1 (BAP1) have documented its importance in suppressing the development of myeloid leukemia. BAP1 is a deubiquitinase (DUB) that acts on histone H2A monoubiquitinated at Lys119 (H2AK119ub), a chromatin modification associated with gene repression. Arenzana et al. report that BAP1 is essential for the development of T cells in the thymus and for promoting peripheral T cell proliferation. Deletion of BAP1 impaired expression of genes associated with cell cycle progression in thymocytes and peripheral T cells. In both cases, the effect of BAP1 deletion was dependent on the DUB activity of BAP1, calling for a closer examination of the role of H2AK119ub in T cell development and differentiation. Sci. Immunol. 3 , eaal1953 (2018).

Metabolic signaling circuits in thymocytes

Thymus Cell differentiation is often accompanied by metabolic changes. Yang et al. report that generation of double-positive (DP) thymocytes, which have both CD4 and CD8 antigens on their surface, from double-negative (DN) thymocytes coincides with dynamic regulation of glycolytic and oxidative

Committing to cytotoxicity

Systems Immunology Cytotoxic CD4+ T cells (CD4-CTLs) were initially identified in patients with chronic viral infections, including dengue virus infection. Patil et al. sequenced the T cell receptors of individual CD4+ T cells from human blood to identify precursors that give rise to CD4-CTL cells. CD4-CTL cells underwent marked clonal expansion, and CD4-CTL precursor cells were characterized by high expression of interleukin-7 receptor. These findings should facilitate improved vaccine design in the context of chronic viral infections. Sci. Immunol. 3 , eaan8664 (2018).

Curbing ILC2 enthusiasm

Skin Inflammation Atopic dermatitis is an allergic disease driven by type 2 immune responses in the skin. Malhotra et al. studied mouse models of dermatitis. They identified the TNF (tumor necrosis factor) family cytokine TL1A (TNF ligand–related molecule 1) and its receptor DR3 (death receptor 3

Setting the stage for attack

Lymphatics There is growing recognition of the importance of stromal cells in shaping immune organs and immune responses. In classical secondary lymphoid organs (SLOs) such as lymph nodes, tonsils, and Peyers patches, fibroblastic reticular cells (FRCs) play an integral part in immune responses. Nonclassical SLOs, including fat-associated lymphoid clusters (FALCs), also have important roles in systemic immunity. Perez-Shibayama et al. report that FRCs in FALCs are both organizational and immunomodulatory. Sci. Immunol. 3 , eaar4539 (2018).

Zooming in on human lymph nodes

HIV Follicular helper T cells (TFH) play an essential role in shaping B cell–mediated antibody responses. Wendel et al. used mass cytometry and T cell receptor sequencing to examine the TFH response in lymph node tissue collected from HIV+ individuals. HIV infection altered the clonality of TFH

Spontaneous HIV controllers

HIV A small number of HIV-infected individuals (<1%) can spontaneously control HIV in the absence of antiretroviral therapy. Because CD4+ and CD8+ T cell responses are thought to contribute to protection, HIV-responsive T cell receptors (TCRs) from these individuals are of considerable interest. Galperin et al. examined how three class II–restricted TCRs observed in spontaneous controllers are capable of binding a Gag peptide in the context of multiple HLA-DR molecules (HLA, human leukocyte antigen). The authors solved the structures of several TCR–peptide–HLA-DR complexes. The findings suggest that the ability of these TCRs to recognize the Gag peptide in the context of multiple HLA-DR allomorphs is shaped by extensive contacts between the TCRs and the peptide itself. Sci. Immunol. 3 , eaat0687 (2018).

Killing without poking holes

Cancer Immunology Given the success of T cell–centric cancer immunotherapies, there is considerable interest in understanding exactly how tumors sometimes evade this form of treatment. Kearney et al. carried out a series of genome-wide CRISPR screens to identify mechanisms of tumor immune evasion from cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Interferon-γ signaling and antigen presentation were critical for CTL-mediated killing of cancer cells, and TNF (tumor necrosis factor) signaling was a key effector mechanism for both CTL and NK cell antitumor activity. The same immune evasion mechanisms arose upon screening with perforin-deficient CTLs, suggesting that tumors evade the immune system by dampening the effects of cytokines, rather than reducing direct killing via perforin. Sci. Immunol. 3 , eaar3451 (2018).

Stitching peptides for presentation

Antigen Presentation Intracellular protein–derived peptides generated by proteasomal degradation are loaded onto major histocompatibility complex (MHC) class I molecules in the endoplasmic reticulum and presented to CD8+ T cells. Although it has been assumed that these peptides are contiguous segments derived from intracellular proteins, recent studies have shown that noncontiguous peptides generated by cis-splicing of two distinct regions of an antigen can be presented by MHC class I molecules. Faridi et al. now demonstrate that MHC class I molecules can present peptides that are generated by the splicing together of segments from two distinct proteins—so-called trans-spliced peptides. Precisely how cis- and trans-spliced peptides are generated and how they contribute to T cell selection and expansion remain to be explored. Sci. Immunol. 3 , eaar3947 (2018).

Giving antibodies a boost

Antibodies Persistent immune activation during chronic infections is often associated with increased generation and deposition of immune complexes. The actions of antibody-based drugs can thus be severely impaired in individuals with chronic infections. Using lymphocytic choriomeningitis virus (LCMV) as a model of chronic infection, Wieland et al. examined how to enhance antibody functions in this setting. The ability of antibodies to deplete target cells was dependent on antigen expression levels. Furthermore, afucosylation of antibodies directed against CD4 and CD8α enhanced their ability to deplete CD4+ and CD8+ T cells in mice persistently infected with LCMV. Whether afucosylation can be universally used to enhance antibody functions during chronic infections remains to be seen. Sci. Immunol. 3 , eaao3125 (2018).