Hobit and Blimp-1 instruct the differentiation of iNKT cells into resident-phenotype lymphocytes after lineage commitment.

iNKT cells are CD1d-restricted T cells that play a pro-inflammatory or regulatory role in infectious and autoimmune diseases. Thymic precursors of iNKT cells eventually develop into distinct iNKT1, iNKT2, and iNKT17 lineages in the periphery. It remains unclear whether iNKT cells retain developmental potential after lineage commitment.

The Transcription Factor Hobit Identifies Human Cytotoxic CD4 T Cells.

The T cell lineage is commonly divided into CD4-expressing helper T cells that polarize immune responses through cytokine secretion and CD8-expressing cytotoxic T cells that eliminate infected target cells by virtue of the release of cytotoxic molecules. Recently, a population of CD4 T cells that conforms to the phenotype of cytotoxic CD8 T cells has received increased recognition. These cytotoxic CD4 T cells display constitutive expression of granzyme B and perforin at the protein level and mediate HLA class II-dependent killing of target cells.

Programs for the persistence, vigilance and control of human CD8 lung-resident memory T cells.

Tissue-resident memory T cells (T cells) in the airways mediate protection against respiratory infection. We characterized T cells expressing integrin α (CD103) that reside within the epithelial barrier of human lungs. These cells had specialized profiles of chemokine receptors and adhesion molecules, consistent with their unique localization.

Clinically Relevant Reactivation of Polyomavirus BK (BKPyV) in HLA-A02-Positive Renal Transplant Recipients Is Associated with Impaired Effector-Memory Differentiation of BKPyV-Specific CD8+ T Cells.

Polyomavirus BK (BKPyV) frequently reactivates in immunosuppressed renal transplant recipients (RTRs) and may lead to graft loss due to BKPyV-induced interstitial nephritis (BKVN). Little is known on the differentiation of CD8+ T cells targeting BKPyV in RTRs. Here we investigated whether BKPyV-specific CD8+ T cell differentiation differs in RTRs with varying degrees of BKPyV reactivation and/or BKVN.

The Adhesion G Protein-Coupled Receptor GPR56/ADGRG1 Is an Inhibitory Receptor on Human NK Cells.

Natural killer (NK) cells possess potent cytotoxic mechanisms that need to be tightly controlled. Here, we explored the regulation and function of GPR56/ADGRG1, an adhesion G protein-coupled receptor implicated in developmental processes and expressed distinctively in mature NK cells. Expression of GPR56 was triggered by Hobit (a homolog of Blimp-1 in T cells) and declined upon cell activation.

Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes.

Tissue-resident memory T (Trm) cells permanently localize to portals of pathogen entry, where they provide immediate protection against reinfection. To enforce tissue retention, Trm cells up-regulate CD69 and down-regulate molecules associated with tissue egress; however, a Trm-specific transcriptional regulator has not been identified. Here, we show that the transcription factor Hobit is specifically up-regulated in Trm cells and, together with related Blimp1, mediates the development of Trm cells in skin, gut, liver, and kidney in mice.

Restoration of T cell function in chronic hepatitis B patients upon treatment with interferon based combination therapy.

Background & Aims: Chronic hepatitis B virus (HBV) infection is characterized by functional impairment of HBV-specific T cells. Understanding the mechanisms behind T cell dysfunction and restoration is important for the development of optimal treatment strategies.

Methods: In this study we have first analysed the phenotype and function of HBV-specific T cells in patients with low viral load (HBV DNA <20,000IU/ml) and spontaneous control over the virus.

Molecular characterization of HCMV-specific immune responses: Parallels between CD8(+) T cells, CD4(+) T cells, and NK cells.

CD8(+) T cells are important for immunity against human cytomegalovirus (HCMV). The HCMV-specific CD8(+) T-cell response is characterized by the accumulation of terminally differentiated effector cells that have downregulated the costimulatory molecules CD27 and CD28. These HCMV-specific CD8(+) T cells maintain high levels of cytotoxic molecules such as granzyme B and rapidly produce the inflammatory cytokine IFN-γ upon activation.

Blimp-1 homolog Hobit identifies effector-type lymphocytes in humans.

Human cytomegalovirus (CMV) induces the formation of effector CD8(+) T cells that are maintained for decades during the latent stage of infection. Effector CD8(+) T cells appear quiescent, but maintain constitutive cytolytic capacity and can immediately produce inflammatory cytokines such as IFN-γ after stimulation. It is unclear how effector CD8(+) T cells can be constitutively maintained in a terminal stage of effector differentiation in the absence of overt viral replication.

Enhanced CD8 T cell responses through GITR-mediated costimulation resolve chronic viral infection.

Chronic infections are characterized by the inability to eliminate the persisting pathogen and often associated with functional impairment of virus-specific T-cell responses. Costimulation through Glucocorticoid-induced TNFR-related protein (GITR) can increase survival and function of effector T cells. Here, we report that constitutive expression of GITR-ligand (GITRL) confers protection against chronic lymphocytic choriomeningitis virus (LCMV) infection, accelerating recovery without increasing pathology.

Infection history determines the differentiation state of human CD8+ T cells.

Unlabelled: After the resolution of the acute phase of infection, otherwise quiescent antigen-experienced CD8(+) T cells confer rapid protection upon reinfection with viral pathogens or, in the case of persistent viruses, help to maintain control of the infection. Depending on the type of virus, antigen-specific CD8(+) T cells have distinct traits, ranging from typical memory cell properties in the case of rapidly cleared viruses to immediate effector functions for persistent viruses. We here show that both the differentiation stage, defined by the expression of cell surface markers, such as CD45RA, CCR7, CD28, and CD27, and distinct expression levels of T-bet and eomesodermin (Eomes) predict the functional profile of antigen-experienced CD8(+) T cells.

The interaction between cytomegalovirus and the human immune system.

Studies on antiviral immunity in man are hampered by the impossibility to standardize the infection as is done in experimental animal studies. An exception is the occurrence of cytomegalovirus infection transmitted by a donor organ into a transplant-recipient, where the time-point of infection is exactly known. Moreover, its strong interaction with the human immune system during evolution and the strong immunogenic properties of this persistent virus, as well as the need for intervention e.

Clonal evolution of CD8+ T cell responses against latent viruses: relationship among phenotype, localization, and function.

Unlabelled: Human cytomegalovirus (hCMV) infection is characterized by a vast expansion of resting effector-type virus-specific T cells in the circulation. In mice, interleukin-7 receptor α (IL-7Rα)-expressing cells contain the precursors for long-lived antigen-experienced CD8(+) T cells, but it is unclear if similar mechanisms operate to maintain these pools in humans. Here, we studied whether IL-7Rα-expressing cells obtained from peripheral blood (PB) or lymph nodes (LNs) sustain the circulating effector-type hCMV-specific pool.

Better safe than sorry: TOB1 employs multiple parallel regulatory pathways to keep Th17 cells quiet.

Th17 cells are key players in antibacterial and antifungal immunity, but have also been implicated in autoimmunity. Interestingly, Th17 cells poorly proliferate upon stimulation, a phenotype that was attributed to a decreased sensitivity to T-cell receptor (TCR) stimulation, and to low IL-2 production by Th17 cells. In this issue of the European Journal of Immunology, Santarlasci et al.

Blood and beyond: properties of circulating and tissue-resident human virus-specific αβ CD8(+) T cells.

CD8(+) αβ T-cell responses form an essential line of defence against viral infections. An important part of the mechanisms that control the generation and maintenance of these responses have been elucidated in experimental mouse models. In recent years it has become clear that CD8(+) T-cell responses in humans not only show similarities, but also display differences to those occurring in mice.

CXCR5+CD4+ follicular helper T cells accumulate in resting human lymph nodes and have superior B cell helper activity.

Although many relevant immune reactions are initiated in the lymph nodes, this compartment has not been systematically studied in humans. Analyses have been performed on immune cells derived from tonsils, but as this tissue is most often inflamed, generalization of these data is difficult. Here, we analyzed the phenotype and function of the human CD4(+) T-cell subsets and lineages in paired resting lymph node and peripheral blood samples.

CMV-specific CD8+ T-cell function is not impaired in chronic lymphocytic leukemia.

In chronic lymphocytic leukemia (CLL), CD8(+) T cells exhibit features of exhaustion and impaired functionality. Yet, reactivations of latent viruses such as cytomegalovirus (CMV) are uncommon in untreated CLL, suggesting that antiviral responses are uncompromised. We analyzed phenotypical and functional characteristics of CMV-specific CD8(+) T cells in CLL patients in comparison with age-matched healthy controls (HCs).

IL-21 and CD40L signals from autologous T cells can induce antigen-independent proliferation of CLL cells.

Chronic lymphocytic leukemia (CLL) cells multiply in secondary lymphoid tissue, but the mechanisms leading to their proliferation are still uncertain. In addition to B-cell receptor (BCR)-triggered signals, other microenvironmental factors might well be involved. In proliferation centers, leukemic B cells are in close contact with CD4(+)CD40L(+) T cells.

Aberrant humoral immune reactivity in DOCK8 deficiency with follicular hyperplasia and nodal plasmacytosis.

Mutations in the DOCK8 gene define the most common form of autosomal-recessive Hyper-IgE-syndrome (AR-HIES/OMIM#243700). In a patient with extensive molluscum contagiosum lesions, a homozygous DOCK8 gene deletion was demonstrated. In-vivo 18-FDG uptake showed multiple non-enlarged lymph nodes without uptake in the spleen.

Characteristics of differentiated CD8(+) and CD4 (+) T cells present in the human brain.

Immune surveillance of the central nervous system (CNS) by T cells is important to keep CNS-trophic viruses in a latent state, yet our knowledge of the characteristics of CNS-populating T cells is incomplete. We performed a comprehensive, multi-color flow-cytometric analysis of isolated T cells from paired corpus callosum (CC) and peripheral blood (PB) samples of 20 brain donors. Compared to PB, CC T cells, which were mostly located in the perivascular space and sporadically in the parenchyma, were enriched for cells expressing CD8.

Phenotypic and functional characterization of circulating polyomavirus BK VP1-specific CD8+ T cells in healthy adults.

The human polyomavirus BK virus (BKV) establishes a latent and asymptomatic infection in the majority of the population. In immunocompromised individuals, the virus frequently (re)activates and may cause severe disease such as interstitial nephritis and hemorrhagic cystitis. Currently, the therapeutic options are limited to reconstitution of the antiviral immune response.

With(out) a little help from my friends: an IL-12/CD40L-mediated feed-forward loop between CD8+ T cells and DCs.

CD40-CD40L interactions are important for both antigen-dependent B-cell differentiation and effector and memory T-cell formation. The prevailing view is that CD40L is expressed on activated CD4(+) T cells, which enables them to provide help to high-affinity B cells in GCs and to license DCs for efficient induction of CD8(+) T-cell responses. Interestingly, CD8(+) T cells themselves can also express CD40L and, in this issue of the European Journal of Immunology, Thiel and colleagues [Eur.

CD27-CD70 costimulation controls T cell immunity during acute and persistent cytomegalovirus infection.

Cytomegaloviruses (CMVs) establish lifelong infections that are controlled in part by CD4(+) and CD8(+) T cells. To promote persistence, CMVs utilize multiple strategies to evade host immunity, including modulation of costimulatory molecules on infected antigen-presenting cells. In humans, CMV-specific memory T cells are characterized by the loss of CD27 expression, which suggests a critical role of the costimulatory receptor-ligand pair CD27-CD70 for the development of CMV-specific T cell immunity.