Human γδ T‐cell responses in infection and immunotherapy: Common mechanisms,common mediators?

Upon receiving the Nobel Prize in Physiology or Medicine in 1987, Susumu Tonegawa referred to the then recent discovery of the γδ T-cell receptor and stated that "while the function of the T cells bearing this receptor is currently unknown (…) these T cells may be involved in an entirely new aspect of immunity". [Tonegawa, S., Scand. J. Immunol. 1993. 38: 303-319]. Twenty-five years of intense research later this ambivalent view still holds true. Immunologists now appreciate that γδ T cells indeed represent a highly intriguing "new aspect of immunity" that is unique and distinct from conventional lymphocytes, yet even scientists in the field still struggle to understand the molecular basis of γδ T-cell responses, especially with respect to the enigmatic mode of antigen recognition. Here, we portray the peculiar responsiveness of human Vγ9/Vδ2 T cells to microorganisms, tumor cells and aminobisphosphonates, in an attempt to integrate the corresponding - and at times confusing - findings into a "theory of everything" that may help explain how such diverse stimuli result in similar γδ T-cell responses via the recognition of soluble low molecular weight phosphoantigens.     

T‐cell migration: a naive paradigm?

Naive T cells have long been thought to recirculate exclusively between secondary lymphoid organs via the lymph and blood. Evidence is now emerging that this view may be too simplistic and that naive T cells routinely traffic through non-lymphoid organs in a manner similar to that of memory T cells, albeit in lower numbers. This represents a fundamental shift in the current paradigm of T-cell migration through different types of tissue. This review summarizes these recent findings, along with the similarities and differences in migratory properties of naive and memory T cells, and discusses how and why naive T cells might access non-lymphoid tissues.     

Going Pro to enhance T‐cell immunogenicity: Easy as π?

MHC class I molecules bind intracellular oligopeptides and present them on the cell surface for CD8⁺ T‐cell activation and recognition. Strong peptide/MHC class I (pMHC) interactions typically induce the best CD8⁺ T‐cell responses; however, many immunotherapeutic tumor‐specific peptides bind MHC with low affinity. To overcome this, immunologists can carefully alter peptides for enhanced MHC affinity but often at the cost of decreased T‐cell recognition. A new report published in this issue of the European Journal of Immunology [Eur. J. Immunol. 2013. 43:3051–3060] shows that the substitution of proline at the third residue (p3P) of a common tumor peptide increases pMHC affinity and complex stability while enhancing T‐cell receptor recognition. X‐ray crystallography indicates that stability is generated through newly introduced CH‐π bonding between p3P and a conserved residue (Y159) in the MHC heavy chain. This finding highlights a previously unappreciated role for CH‐π bonding in MHC peptide binding, and importantly, arms immunologists with a novel and possibly general approach for increasing pMHC stability without compromising T‐cell recognition.     

Is ALK‐gene rearrangement overlooked in primary gastrointestinal T‐cell lymphomas? About two cases

A 41‐year‐old male patient with a history of ankylosing spondylitis and Crohn disease, treated with immunomodulators and disease‐modifying drugs, was diagnosed with a primary intestinal T‐cell lymphoma that followed a 7.5‐year‐course. This transmural proliferation lacked cytological characteristics of anaplastic large cell lymphoma (ALCL), and was CD8‐positive, and CD30‐ and anaplastic lymphoma kinase (ALK)‐negative by immunohistochemistry (IHC). However, ALK‐gene rearrangement (ALK‐gr) was detected by fluorescence in situ hybridization (FISH) in both initial and persistent disease. The possibility of indolent T‐cell lymphoproliferative disease of the gastrointestinal tract with atypical features (transmural involvement) related to ALK‐gr was suggested. A previous case of aggressive ‘enteropathy‐associated ALCL’ in the context of celiac disease was recently reported, which also lacked anaplastic morphology, and where CD30 and ALK expression was incidentally demonstrated by IHC, and ALK‐gr subsequently confirmed by FISH. These two recent cases represent two distinct rare entities pertaining to the group of primary intestinal T‐cell lymphomas, and they both show unexpected ALK‐gr. This suggests that ALK‐gr has been overlooked in the group of primary intestinal T‐cell lymphomas. Performing IHC and FISH tests for ALK‐gr in primary gastrointestinal T‐cell lymphomas might be of importance, particularly with the advancement of targeted therapy that could impact treatment and prognosis.     

Therapeutic anti‐integrin (α4 and αL) monoclonal antibodies: two‐edged swords?

Anti-alpha4 and anti-alphaL integrin chain monoclonal antibodies have shown a clear-cut beneficial effect in different animal models of autoimmune and inflammatory disorders as well as in human diseases, including multiple sclerosis, inflammatory bowel disease, and psoriasis. It has been widely assumed that this therapeutic effect is mainly consequence of the blockade of leucocyte adhesion to endothelium, inhibiting thus their extravasation and the inflammatory phenomenon. However, it is evident that both alpha4beta1 (very late antigen-4) and alphaLbeta2 (leucocyte function-associated antigen-1) integrins have additional important roles in other immune phenomena, including the formation of the immune synapse and the differentiation of T helper 1 lymphocytes. Therefore, it is very feasible that the long-term administration of blocking agents directed against these integrins to patients with inflammatory/autoimmune conditions may have undesirable or unexpected effects.     

The Humoral Response in TCR α–/– Mice. Can γδ‐T Cells Support the Humoral Immune Response?

An optimal humoral response requires T-cell help; however, it has been questioned if this help comes exclusively from alphabeta-T cells or whether gammadelta-T cells also contribute. We have attempted to answer this question by studying the humoral response in T-cell receptor alpha-chain knockout (alpha-/-) mice, which lack the alphabetaT cell subset. Two model antigens were used to characterize the response: the thymus-independent (TI) antigen native dextran B512 (Dx), and the thymus-dependent (TD) antigen heat shock protein (HSP65) from Mycobacterium tuberculosis. When challenged with Dx, the alpha-/- mice elicited a strong antibody response and formed rudimentary germinal centres (GCs), a T-cell dependent reaction. In contrast, the humoral response to HSP65 was poor. However, alpha-/- mice became primed when challenged with HSP65, because when supplemented with wild-type thymocytes, the antigen-primed animals were able to mount a stronger response than the nonprimed ones when challenged with HSP65. A crucial step seems to be the collaboration between gammadeltaT cells and antigen presenting cells (APCs), as splenocytes from alpha-/- mice were able to respond to HSP65 in an environment containing primed-APCs. Based on these results, we propose a model for B-cell activation in the alpha-/- mice.     

The Multifunctionality of Human Vγ9Vδ2 γδ T Cells: Clonal Plasticity or Distinct Subsets?

The dominant subset of γδ T cells in human peripheral blood expresses Vγ9 paired with Vδ2 as variable TCR elements. Vγ9Vδ2 T cells recognize pyrophosphates derived from the microbial non‐mevalonate isoprenoid biosynthesis pathway at pico‐ to nanomolar concentrations. Structurally related pyrophosphates are generated in eukaryotic cells through the mevalonate pathway involved in protein prenylation and cholesterol synthesis. However, micromolar concentrations of endogenous pyrophosphates are required to be recognized by Vγ9Vδ2 T cells. Such concentrations are not produced by normal cells but can accumulate upon cellular stress and transformation. Therefore, many tumour cells are susceptible to γδ T cell–mediated lysis owing to the overproduction of endogenous pyrophosphates. This explains why Vγ9Vδ2 T cells contribute to both anti‐infective and anti‐tumour immunity. Ex vivo analysed Vγ9Vδ2 T cells can be subdivided on the basis of additional surface markers, including chemokine receptors and markers for naïve and memory T cells. At the functional level, Vγ9Vδ2 T cells produce a broad range of cytokines, display potent cytotoxic activity, regulate αβ T cell responses, and – quite surprisingly – can act as professional antigen‐presenting cells. Thus, an exceptional range of effector functions has been assigned to a population of T cells, which all recognize invariant exogenous or endogenous pyrophosphates that are not seen by any other immune cell. Here, we discuss whether this plethora of effector functions reflects the plasticity of individual Vγ9Vδ2 T cells or can be assigned to distinct subsets.     

Diagnostic dilemmas in HLH: Can T‐cell phenotyping help?

The diagnosis of hemophagocytic lymphohistiocytosis (HLH) can be a difficult one, and the distinction between primary versus secondary HLH can be particularly challenging during the early stages of diagnosis. This distinction is important to make as primary HLH requires allogeneic hematopoietic cell transplantation for a definitive cure. Flow cytometric screening tests for many of the genetic forms of HLH are available. However, not all patients with primary HLH are captured by these screening tests, due to the fact that no screening test is 100% sensitive, and additionally, some patients with “primary” forms of HLH may have mutations in genes which are yet to be discovered. In this issue of the European Journal of Immunology, Ammann et al. [Eur. J. Immunol. 2017. 47 : 364–373] compare T‐cell phenotype patterns among patients with primary and secondary HLH, and find that assessment of T‐cell activation and differentiation may assist with the diagnosis of HLH. Furthermore, this phenotypic analysis has the potential to help make the important distinction between primary and secondary HLH.     

Clear cell renal cell carcinoma with wild‐type von Hippel‐Lindau gene: a non‐existent or new tumour entity?

The current World Health Organisation (WHO) classification of renal tumours is based on characteristic histological features or specific molecular alterations. von Hippel‐Lindau (VHL) alteration is the hallmark of clear cell renal cell carcinoma (RCC). After identification of the MiT translocation family of tumours, clear cell papillary renal cancer and others, the group of ccRCC with wild‐type VHL is small. TCEB1 mutation combined with chromosome 8q loss is an emerging tumour entity with wild‐type VHL. Inactivation of TCEB1 increases HIF stabilisation via the same mechanism as VHL inactivation. Importantly, recent molecular analyses suggest the existence of another ‘VHL wild‐type’ evolutionary subtype of clear cell RCC in addition to TCEB1 mutated RCC and clear cell papillary renal cancer. These tumours are characterised by an aggressive behaviour, high tumour cell proliferation rate, elevated chromosomal instability and frequent presence of sarcomatoid differentiation. Future clinicopathological studies will have to provide data to determine whether TCEB1 tumours and clear cell RCC with wild‐type VHL are separate tumour entities or represent variants of a clear cell RCC tumour family.     

T‐cell exhaustion due to persistent antigen: Quantity not quality?

T-cell exhaustion is characterized by failure to respond to a persistent antigen and is a hallmark of chronic infections and cancer. Here, we discuss several recent reports on T-cell exhaustion, including one in this issue of the European Journal of Immunology where Richter et al. [Eur. J. Immunol. 42:2290-2304] examine the importance of the amount of persistent antigen versus the cell type presenting it to induce CD8(+) T-cell exhaustion, and the consequences for host survival during chronic viral infection.     

Immunological decision‐making: how does the immune system decide to mount a helper T‐cell response?

Aberrant T-cell responses underpin a range of diseases, including asthma and allergy and autoimmune diseases. Pivotal immune elements of these diseases are the development of antigen-specific effector T-helper type 2 (Th2) cells, Th1 cells, or the recently defined Th17 cells that are associated with the clinical features and disease progression. In order to identify crucial processes in the pathogenesis of these diseases it is critical to understand how the development of these T cells occurs. The phenotype of a polarized T-cell that differentiates from a naïve precursor is determined by the complex interaction of antigen-presenting cells with naïve T cells and involves a multitude of factors, including the dominant cytokine environment, costimulatory molecules, type and load of antigen presented and a plethora of signaling cascades. The decision to take the immune response in a certain direction is not made by one signal alone, instead many different elements act synergistically, antagonistically and through positive feedback loops to activate a Th1, Th2, or Th17 immune response. The elucidation of the mechanisms of selection of T-cell phenotype will facilitate the development of therapeutic strategies to intervene in the development of deleterious T-cell responses. This review will focus on the pathways and key factors responsible for the differentiation of the various subsets of effector CD4 T cells. We will primarily discuss what is known of the Th1 and Th2 differentiation pathways, while also reviewing the emerging research on Th17 differentiation.     

Protection from autoimmunity: Immunological indifference versus T‐cell mediated suppression?

A long-held dogma was that immune tolerance could only be achieved through central deletion of potentially reactive cells at their site of origin, a concept supported by the direct demonstration of natural negative selection in bone marrow and thymus; however, it is now extensively documented that although deletion mechanisms ensure the elimination of most autoreactive cells, this purging is far from complete.There are major immune mechanisms that ensure tolerance in the periphery which are clearly non-deletional. A paper in this issue of the European Journal of Immunology demonstrates that T cell-mediated immunoregulation involving in particular the CTLA-4 signaling pathway plays a key role in controlling the pathogenic potential of fully differentiated autoreactive T cells.     

TGFβ—a role in systemic sclerosis?

Systemic sclerosis (SSc) is a multisystem connective tissue disorder in which there is progressive fibrosis. Transforming growth factor beta (TGFβ) has wide-ranging cellular actions. It is a potent chemoattractant for human dermal fibroblasts, from which it may induce synthesis of collagen, which suggests that it may have a central role to play in the pathogenesis of SSc. This is supported to some extent by in vitro studies. SSc fibroblasts produce more collagens and fibronectin than normal fibroblasts and elevated TIMP levels have been observed, all of which could be explained on the basis of TGFβ stimulation of fibroblasts. Some studies have suggested that fibroblasts are the source of TGFβ. However, the serum of patients with SSc is cytotoxic to endothelial cells, which could culminate in TGFβ synthesis by them, with secondary fibroblast stimulation. The role of TGFβ remains elusive, although it would seem an ideal candidate as a mediator of fibrosis in systemic sclerosis. © 1998 John Wiley & Sons, Ltd.