Axel Kallies

The Walter and Eliza Hall Institute of Medical Research · Division of Immunology

Targeting epigenetic regulators prevents T cell exhaustion

CD8⁺ T cells control tumors but inevitably become dysfunctional in the tumor microenvironment. Here, we show that sodium chloride (NaCl) counteracts T cell dysfunction to promote cancer regression. NaCl supplementation during CD8⁺ T cell culture induced effector differentiation, IFN-γ production and cytotoxicity while maintaining the gene networks...

Cytotoxic CD8 + T cells, essential in combating viral infections and cancer, become dysfunctional from prolonged antigen exposure. Precursors of exhausted T (T PEX ) cells are pivotal in sustaining immune responses in chronic diseases and mediating immunotherapy efficacy. They also control viral infection within B-cell follicles, facilitated by CXC...

Cytotoxic CD8 + T cells, essential in combating viral infections and cancer, become dysfunctional from prolonged antigen exposure. Precursors of exhausted T (T PEX ) cells are pivotal in sustaining immune responses in chronic diseases and mediating immunotherapy efficacy. They also control viral infection within B-cell follicles, facilitated by CXC...

Adipose tissue stores excess energy and produces a broad range of factors that regulate multiple physiological processes including systemic energy homeostasis. Visceral adipose tissue (VAT) plays a particularly important role in glucose metabolism as its endocrine function underpins food uptake and energy expenditure. Caloric excess triggers VAT in...

Cytotoxic CD8+ T cells, essential in combating viral infections and cancer, become dysfunctional from prolonged antigen exposure. Precursors of exhausted T (TPEX) cells are pivotal in sustaining immune responses in chronic diseases and mediating immunotherapy efficacy. They also control viral infection within B-cell follicles, facilitated by CXCR5...

Two new species, Taikona gaoligongshana Yu, Arita & Kallies, sp. nov. and Taikona extraordinaria Yu, Kallies & Arita sp. nov. are described from Yunnan Province, China. Illustrations of the holotypes and the male genitalia are provided, along with a key to all currently known species of the genus. DNA barcoding sequences are also provided.

T follicular helper (T FH ) cells are essential for effective antibody responses, but deciphering the intrinsic wiring of mouse T FH cells has long been hampered by the lack of a reliable protocol for their generation in vitro. We report that transforming growth factor–β (TGF-β) induces robust expression of T FH hallmark molecules CXCR5 and Bcl6 in...

Visceral adipose tissue (VAT) is an energy store and endocrine organ critical for metabolic homeostasis. Regulatory T (Treg) cells restrain inflammation to preserve VAT homeostasis and glucose tolerance. Here, we show that the VAT harbors two distinct Treg cell populations: prototypical serum stimulation 2-positive (ST2⁺) Treg cells that are enrich...

Persistent antigen exposure results in the differentiation of functionally impaired, also termed exhausted, T cells which are maintained by a distinct population of precursors of exhausted T (T PEX ) cells. T cell exhaustion is well studied in the context of chronic viral infections and cancer, but it is unclear whether and how antigen-driven T cel...

Ikaros transcription factors are essential for adaptive lymphocyte function, yet their role in innate lymphopoiesis is unknown. Using conditional genetic inactivation, we show that Ikzf1/Ikaros is essential for normal natural killer (NK) cell lymphopoiesis and IKZF1 directly represses Cish, a negative regulator of interleukin-15 receptor resulting...

Skin-resident CD8 ⁺ T cells include distinct interferon-γ–producing [tissue-resident memory T type 1 (T RM 1)] and interleukin-17 (IL-17)–producing (T RM 17) subsets that differentially contribute to immune responses. However, whether these populations use common mechanisms to establish tissue residence is unknown. In this work, we show that T RM 1...

Background CD8+ T cell responses to chronic infection and cancer are sustained by stem-like precursors of exhausted T (Tpex) cells that express high levels of memory-related transcriptional regulators including TCF1 and ID3. Methods Here, we take advantage of the murine acute and chronic Lymphocytic Choriomengitis Virus (LCMV) as well as B16F10 ca...

The differentiation of naive CD8⁺ T lymphocytes into cytotoxic effector and memory CTL results in large-scale changes in transcriptional and phenotypic profiles. Little is known about how large-scale changes in genome organization underpin these transcriptional programs. We use Hi-C to map changes in the spatial organization of long-range genome co...

Memory CD8+ T cells can be broadly divided into circulating (TCIRCM) and tissue-resident memory T (TRM) populations. Despite well-defined migratory and transcriptional differences, the phenotypic and functional delineation of TCIRCM and TRM cells, particularly across tissues, remains elusive. Here, we utilized an antibody screening platform and mac...

The presence of immune cells in non-lymphoid tissues throughout the body is vital in the fight against infections and cancer. Yet, a detailed map of immune cell distribution and interactions throughout the body is lacking. To address this gap, we harmonised and annotated 29 million cells across 12,981 single-cell RNA sequencing samples covering 45...

CD8+ T cell fate is tightly regulated by epigenetic modification. In this issue of Immunity, McDonald et al. and Baxter et al. demonstrate that the chromatin remodeling complexes cBAF and PBAF control proliferation, differentiation, and function of cytotoxic T cells in response to infection as well as cancer.

Antiviral CD8⁺ T cell immunity depends on the integration of various contextual cues, but how antigen-presenting cells (APCs) consolidate these signals for decoding by T cells remains unclear. Here, we describe gradual interferon-α/interferon-β (IFNα/β)-induced transcriptional adaptations that endow APCs with the capacity to rapidly activate the tr...

The differentiation of naïve CD8 ⁺ cytotoxic T lymphocytes (CTLs) into effector and memory states results in large scale changes in transcriptional and phenotypic profiles. Little is known about how large-scale changes in genome organisation reflect or underpin these transcriptional programs. We utilised Hi-C to map changes in the spatial organisat...

A new species, Oligophlebia hibiscivora Yu, Kallies & Arita sp. nov., is described from south-eastern China. Superficially, it is similar to Oligophlebia insurgia Kallies, 2020 but it differs by external features of the abdomen as well as the male genitalia characters. The larva of this new species feed in Hibiscus tiliaceus L. (Malvaceae) and was...

Ikaros family transcription factors regulate lymphocyte biology and are targets of the immunomodulatory imide drugs (IMiDs) for hematological maligancies. Ikaros (Ikzf1/IKZF1) is the most broadly expressed family member in lymphocytes, yet its role in innate lymphopoiesis was unknown. Here we used conditional gene inactivation to reveal that Ikaros...

This commentary article highlights two recently published studies, which for the first time revealed the immunological underpinnings of sex‐bias in cancer incidence and mortality. These studies showed that the androgen receptor restrains anti‐tumour immunity in males by repressing cytotoxic genes in CD8+ T cells.

CD8+ T cells that respond to chronic viral infections or cancer are characterized by the expression of inhibitory receptors such as programmed cell death protein 1 (PD-1) and by the impaired production of cytokines. This state of restrained functionality—which is referred to as T cell exhaustion1,2—is maintained by precursors of exhausted T (TPEX)...

Aberrant expression of the proto-oncogene BCL6 is a driver of tumorigenesis in diffuse large B cell lymphoma (DLBCL). Mice overexpressing BCL6 from the B cell-specific immunoglobulin heavy chain μ intron promoter (Iμ-Bcl6Tg/+) develop B cell lymphomas with features typical of human DLBCL. While B cell lymphoma development in these mice is tightly c...

The tumor microenvironment (TME) contains a rich source of nutrients that sustains cell growth and facilitate tumor development. Glucose and glutamine in the TME are essential for the development and activation of effector T cells that exert antitumor function. Immunotherapy unleashes T cell antitumor function, and although many solid tumors respon...

Reinvigoration of exhausted CD8⁺ T (Tex) cells by checkpoint immunotherapy depends on the activation of precursors of exhausted T (Tpex) cells, but the local anatomical context of their maintenance, differentiation, and interplay with other cells is not well understood. Here, we identified transcriptionally distinct Tpex subpopulations, mapped thei...

Understanding the complex elements affecting signal resolution in cytometry is key for quality experimental design and data. In this study we incorporate autofluorescence as a contributing factor to our understanding of resolution in cytometry and corroborate its impact in fluorescence signal detection through mathematical predictions supported by...

Targeting the potent immunosuppressive properties of FOXP3 ⁺ regulatory T cells (T regs ) has substantial therapeutic potential for treating autoimmune and inflammatory diseases. Yet, the molecular mechanisms controlling T reg homeostasis, particularly during inflammation, remain unclear. We report that caspase-8 is a central regulator of T reg hom...

Glucose is a vital source of energy for all mammals. The balance between glucose uptake, metabolism and storage determines the energy status of an individual, and perturbations in this balance can lead to metabolic diseases. The maintenance of organismal glucose metabolism is a complex process that involves multiple tissues, including adipose tissu...

Tissue-resident memory T (TRM) cells are non-recirculating cells that exist throughout the body. Although TRM cells in various organs rely on common transcriptional networks to establish tissue residency, location-specific factors adapt these cells to their tissue of lodgment. Here we analyze TRM cell heterogeneity between organs and find that the...

CD8+ tissue-resident memory T (TRM) cells play crucial roles in defense against infections and cancer and have been implicated in autoimmune diseases such as psoriasis. In mice and humans, they exist in all nonlymphoid organs and share key characteristics across all tissues, including downregulation of tissue egress and lymph node homing pathways....

Immunotherapy success in colorectal cancer (CRC) is mainly limited to patients whose tumors exhibit high microsatellite instability (MSI). However, there is variability in treatment outcomes within this group, which is in part driven by the frequency and characteristics of tumor infiltrating immune cells. Indeed, the presence of specific infiltrati...

Antigen-specific CD8⁺ T cells in chronic viral infections and tumors functionally deteriorate, a process known as exhaustion. Exhausted T cells are sustained by precursors of exhausted (Tpex) cells that self-renew while continuously generating exhausted effector (Tex) cells. However, it remains unknown how Tpex cells maintain their functionality. H...

Chronic stimulation of CD8 ⁺ T cells triggers exhaustion, a distinct differentiation state with diminished effector function. Exhausted cells exist in multiple differentiation states, from stem-like progenitors that are the key mediators of the response to checkpoint blockade, through to terminally exhausted cells. Due to its clinical relevance, th...

The heterogeneous pool of tissue-resident lymphocytes in solid organs mediates infection responses and supports tissue integrity and repair. Their vital functions in normal physiology suggest an important role in solid organ transplantation; however, their detailed examination in this context has not been performed. Here, we report the fate of mult...

Selective targeting of BCL2 with the BH3-mimetic venetoclax is proving transformative for patients with various leukemias. TP53 controls apoptosis upstream from where BCL2 and its pro-survival relatives, such as MCL1, act. Therefore, targeting these pro-survival proteins could trigger apoptosis across diverse blood cancers, irrespective of TP53 mut...

The antitumour activity of endogenous or adoptively transferred tumour-specific T cells is highly dependent on their differentiation status. It is now apparent that less differentiated T cells compared with fully differentiated effector T cells have better antitumour therapeutic effects owing to their enhanced capacity to expand and their long-term...

A Correction to this paper has been published: https://doi.org/10.1038/s41586-020-2251-7

A new clearwing moth, Paranthrenella cinnamoma sp. nov., is described from southern China. Adults and genitalia are illustrated, DNA barcodes provided, and potential damage to Cinnamomum trees (Lauraceae) is described. Paranthrenella mushana (Matsumura, 1931) comb. nov. is transferred from Synanthedon Hübner, [1819]. A checklist of the species of P...

Antiviral CD8⁺ T cell responses are characterized by an initial activation/priming of T lymphocytes followed by a massive proliferation, subset differentiation, population contraction and the development of a stable memory pool. The transcription factor BATF3 has been shown to play a central role in the development of conventional dendritic cells,...

NK cells play critical roles in protection against haematological malignancies but can acquire a dysfunctional state, which limits anti-tumour immunity. However, the underlying reasons for this impaired NK cell function remain to be uncovered. We found that NK cells in aggressive B cell lymphoma underwent substantial transcriptional reprogramming a...

MR1-restricted mucosal-associated invariant T (MAIT) cells play a unique role in the immune system. These cells develop intrathymically through a three-stage process, but the events that regulate this are largely unknown. Here, using bulk and single-cell RNA sequencing–based transcriptomic analysis in mice and humans, we studied the changing transc...

Interactions with the microbiota influence many aspects of immunity, including immune cell development, differentiation and function. Here we examined the impact of microbiota on one of the key functions of CD8+T cells, the transition to long-lived and protective memory. Antigen-activated CD8+T cells transferred into germ-free mice failed to transi...

Adipose tissue is an energy store and a dynamic endocrine organ1,2. In particular, visceral adipose tissue (VAT) is critical for the regulation of systemic metabolism3,4. Impaired VAT function—for example, in obesity—is associated with insulin resistance and type 2 diabetes5,6. Regulatory T (Treg) cells that express the transcription factor FOXP3 a...

The molecular mechanisms responsible for the high immunosuppressive capacity of CD4+ regulatory T cells (Tregs) in tumors are poorly known. High-dimensional single cell profiling of T cells from chemotherapy-naïve individuals with non-small cell lung cancer identified the transcription factor IRF4 as specifically expressed by a subset of intratumor...

A new species of Toleria Walker, [1865], T. aritai Ogane & Kallies spec. nov., is described from Vietnam and Laos. Superficially, it resembles species of the genus Dasysphecia Hampson, 1919 but differs by venation and genitalia characters. The tribe Cissuvorini is briefly reviewed. Chimaerosphecia Strand, [1916] syn. rev. is considered a younger su...

Differentiation and homeostasis of Foxp3+ regulatory T (Treg) cells are strictly controlled by T-cell receptor (TCR) signals; however, molecular mechanisms that govern these processes are incompletely understood. Here we show that Bach2 is an important regulator of Treg cell differentiation and homeostasis downstream of TCR signaling. Bach2 prevent...

IL-17-producing CD8+ (Tc17) cells are enriched in active lesions of patients with multiple sclerosis (MS), suggesting a role in the pathogenesis of autoimmunity. Here we show that amelioration of MS by dimethyl fumarate (DMF), a mechanistically elusive drug, associates with suppression of Tc17 cells. DMF treatment results in reduced frequency of Tc...

We here describe a new species, Lamellisphecia minwangi Arita & Kallies sp. nov., from Nanling, Guangdong, southern China. Furthermore, we provide new records of Lemellisphecia Kallies & Arita, 2004 species from south-east Asia, with L. champaensis Kallies & Arita, 2004 recorded for Laos and L. haematinea Kallies & Arita, 2004 recorded for Myanmar...

Despite the key role that antibodies play in protection, the cellular processes mediating the acquisition of humoral immunity against malaria are not fully understood. Using an infection model of severe malaria, we find that germinal center (GC) B cells upregulate the transcription factor T-bet during infection. Molecular and cellular analyses reve...

The transcription factor interferon regulatory factor 4 (IRF4) is critical for the development, maintenance, and function of plasma cells. The mechanism by which IRF4 exerts its action in mature plasma cells has been elusive due to the death of all such cells upon IRF4 loss. While we identify apoptosis as a critical pathway for the death of plasma...

Three new species of the genus Paradoxecia Hampson, 1919 (Lepidoptera: Sesiidae) are described from China: Paradoxecia kishidai Yu & Arita sp. nov., Paradoxecia polyzona Yu & Kallies sp. nov. and Paradoxecia beibengensis Yu & Kallies sp. nov. Illustrations of the holotypes and the male genitalia are provided along with a key to all currently known...

Cytotoxic T cell immunity in response to chronic infections and tumours is maintained by a specialized population of CD8⁺ T cells that exhibit hallmarks of both exhausted and memory cells and give rise to terminally differentiated exhausted effector cells that contribute to viral or tumour control. Importantly, recent work suggests these cells, whi...

‘T cell exhaustion’ is a broad term that has been used to describe the response of T cells to chronic antigen stimulation, first in the setting of chronic viral infection but more recently in response to tumours. Understanding the features of and pathways to exhaustion has crucial implications for the success of checkpoint blockade and adoptive T c...

Heliozelidae are a cosmopolitan family of small, day‐flying moths, and include some pest species of commercial crops. Overall, the family is poorly known and lacks a well‐resolved phylogeny. Previous molecular and taxonomic work has revealed rich undescribed diversity within the family, particularly in Australia; however, the relationships amongst...

Melittia newara Moore, 1879 is newly recorded from southwestern China. Two male specimens were collected in Yipinglang, Yunnan, China. Photographs of the adult and illustrations of the male genitalia are provided.

Microbiota modulate the immune system and recent studies suggest a functional relationship between microbiota, its metabolites and CD8+ T cells, but whether this link is also relevant for CD8+ T cell memory is unclear. We show that antigen-activated CD8+ T cells transferred into germ-free mice had transcriptional impairments in oxidative metabolism...

The differentiation of regulatory T (Treg) cells is strictly controlled by T cell receptor (TCR) signals. However, the downstream regulators of this process are incompletely understood. Here we have found that Bach2 blocks the genomic binding of the TCR-induced transcription factor IRF4, attenuating TCR-dependent transcriptional programs to fine-tu...

Foxp3⁺ regulatory T cells (Treg cells) are crucial for the maintenance of immune homeostasis both in lymphoid tissues and in non-lymphoid tissues. Here we demonstrate that the ability of intestinal Treg cells to constrain microbiota-dependent interleukin (IL)-17–producing helper T cell (TH17 cell) and immunoglobulin A responses critically required...

Somatically acquired mutations in PHF6 (plant homeodomain finger 6) frequently occur in hematopoietic malignancies and often coincide with ectopic expression of TLX3. However, there is no functional evidence to demonstrate whether these mutations contribute to tumorigenesis. Similarly, the role of PHF6 in hematopoiesis is unknown. We report here th...

Table S2. Differentially Expressed Genes in Wild-Type Foxp3+ Treg Cells Versus Blimp1-Deficient Foxp3+ Treg Cells Isolated from the CNS of Mixed Bone Marrow Chimeric Mice (Wild-Type [CD45.1] Plus Blimp1ΔFoxp3 [CD45.2]) at the Peak of EAE, Related to Figure 3

Table S1. Differentially Expressed Genes in Wild-Type Foxp3+ Treg Cells Isolated from the CNS or the Spleen of Mice at the Peak of EAE, Related to Figure 1

A wide array of chemokine receptors, including CCR2, are known to control Treg migration. Here, we report that CCR2 regulates Tregs beyond chemotaxis. We found that CCR2 deficiency reduced CD25 expression by FoxP3+ Treg cells. Such a change was also consistently present in irradiation chimeras reconstituted with mixed bone marrow from wild-type (WT...

We here describe a new ghost moth (Hepialidae) species, Pharmaciscantabricussp. n. from the Picos de Europa National Park, Cantabria, in northern Spain. The new species belongs to a group of mostly day-flying species that are restricted to the European Alps and some mountain ranges of southern Europe. Based on morphology and analysis of mitochondri...

BTB and CNC Homology 1, Basic Leucine Zipper Transcription Factor 2 (BACH2) is a transcription factor best known for its role in B cell development. More recently, it has been associated with T cell functions in inflammatory diseases, and has been proposed as a master transcriptional regulator within the T cell compartment. In this study, we employ...

CD8 T cells acquire cytotoxic molecules including granzyme B during effector differentiation. Both tissue‐resident memory CD8 T cells (Trm) and circulating CD45RA+ effector‐type T cells (Temra) cells have the ability to retain granzyme B protein expression into the memory phase, but it is unclear how this persistence of cytolytic activity is regula...

The mechanistic understanding of gene-expression regulation is still evolving. In this issue of Immunity, Hosokawa et al. (2018) reveal that PU.1 represses transcription indirectly during early T cell development by "stealing" other regulators such as Runx1 and Satb1 from their DNA binding sites.

A new species of forester moths, Pollanisus hyacinthus sp. nov., is described from Kangaroo Island, South Australia. It is similar to Pollanisus isolatus Tarmann, 2004 and Pollanisus cyanota (Meyrick, 1886) but differs in several external characters and in the genitalia.