Antigen presentation by T cells versus professional antigen-presenting cells (APC): differential consequences for T cell activation and subsequent T cell-APC interactions.

We compared the effects of antigen (Ag) presentation by T cells and professional antigen-presenting cells (APC) on T cell proliferation, cytokine production and surface molecule expression. Ag presentation by T cells (T-T presentation) induced an initial T cell activation phase as measured by proliferation and IL-2 production. These activated T cells became anergic upon antigenic restimulation by professional APC, as shown by a failure to proliferate or produce IL-2 or IFN-gamma. Interestingly, such T cells were not intrinsically defective in their signal transduction pathways since they did proliferate and produce cytokines upon restimulation with mitogenic stimuli. Flow cytometric analysis revealed a more profound TCR and CD3 down-regulation during T-T presentation than during APC-T presentation. However, no up-regulation of CD80, CD86, CD45RC and OX40 (CD134) was observed on T cells during T-T presentation or subsequent antigenic restimulation of anergic T cells in the presence of professional APC, whereas increased expression of these molecules was observed during professional APC-T presentation of non-anergic T cells. The impaired expression of co-stimulatory and activation molecules on T cells after T-T presentation of Ag might lead to altered interactions between T cells and professional APC upon antigenic restimulation. We propose that T cell anergy is a functional consequence of these altered T cell-APC interactions.     

SLAM family receptors and the SLAM-associated protein (SAP) modulate T cell functions

One or more of the signaling lymphocytic activation molecule (SLAM) family (SLAMF) of cell surface receptors, which consists of nine transmembrane proteins, i.e., SLAMF1-9, are expressed on most hematopoietic cells. While most SLAMF receptors serve as self-ligands, SLAMF2 and SLAMF4 use each other as counter structures. Six of the receptors carry one or more copies of a unique intracellular tyrosine-based switch motif, which has high affinity for the single SH2-domain signaling molecules SLAM-associated protein and EAT-2. Whereas SLAMF receptors are costimulatory molecules on the surface of CD4+, CD8+, and natural killer (NK) T cells, they also involved in early phases of lineage commitment during hematopoiesis. SLAMF receptors regulate T lymphocyte development and function and modulate lytic activity, cytokine production, and major histocompatibility complex-independent cell inhibition of NK cells. Furthermore, they modulate B cell activation and memory generation, neutrophil, dendritic cell, macrophage and eosinophil function, and platelet aggregation. In this review, we will discuss the role of SLAM receptors and their adapters in T cell function, and we will examine the role of these receptors and their adapters in X-linked lymphoproliferative disease and their contribution to disease susceptibility in systemic lupus erythematosus.     

The involvement of the cell matrix receptors, or VLA integrins, in the morphogenetic behavior of normal and malignant cells is gradually being uncovered

The VLA-Integrins are members of a family of cell surface receptors that recognize Arg-Gly-Asp containing ligands and that allow cells to bind extracellular matrix molecules such as fibronectin, laminin, and collagens. These interactions reorganize the topographic distribution of the receptors at the cell surface and are relayed to the cytoplasm and even to the cell nucleus. Coordinated organization of the intracellular cytoskeleton, cell spreading on the matrix, and movement of the cells along concentration gradients of these matrix molecules are the result of these interactions. Evidence exists that the migration of embryonic cells, platelet activation on endothelial defects, and the invasion of fibroblasts, lymphoid cells, and epithelial cells during wound healing are facilitated by Integrin-matrix interactions. Moreover, deficiency in the synthesis of a particular Integrin subunit or the inappropriate expression of one or a few members of this family might contribute fundamentally to invasion and metastasis of malignant cells. Although extensive information is available on the structure of the common beta 1 subunit and on the function of the fibronectin receptor, in particular, the other five members of the very late antigen family, their respective alpha subunits and their function as cell surface receptors remain poorly understood. The rationale for having at least six different receptors on some cells, how they might collaborate, and to what end remains unknown. Finally, the interaction of these cell surface receptors and the modulation of their affinity for their ligand by other cell surface or extracellular matrix components such as heparan sulfate, gangliosides a.o. have been barely touched upon. It can be predicted that these molecules and their interaction with the extracellular matrix will provide a key to the understanding of many normal and malignant morphogenetic cellular properties.     

A monoclonal antibody blocking human T cell function

The possible functional role of T cell surface antigens defined by monoclonal antibodies was investigated. Five monoclonal anti-T cell reagents as well as an anti-Ia and anti-beta 2-microglobulin antibody were examined for their effect on T cell function. It was shown that an antibody termed anti-T3, reactive with all peripheral T cells, blocked T cell proliferative responses to soluble and cell surface antigens. This inhibition was seen when T lymphocytes were treated with as few as 10(4) anti-T3 molecules per cell. Although anti-T3 could block the generation of cytotoxic T cells in mixed lymphocyte culture, once generated, anti-T3 had no effect on cytotoxicity. In addition, anti-T3 abrogated the ability of T cells to provide help to B cells in a pokeweed mitogen-driven immunoglobulin system. More importantly, these functional effects were not seen with the other monoclonal antibodies. Both the appearance of this antigen in intrathymic ontogeny and its critical role in T cell function suggests that the T3 molecule is related to an important antigen recognition receptor or cell-cell interactions molecule.     

Cloned human T cells synthetize Ia molecules and can function as antigen presenting cells

TNP-specific proliferative cloned human T cell lines were investigated for their synthesis and cell surface expression of HLA-DR molecules and for their capacity to function as antigen presenting cells. Utilizing radioactive amino acid precursors for metabolic labeling, these studies demonstrated endogenous synthesis of HLA-DR molecules by cloned T cells, which by two-dimensional gel electrophoresis were similar to HLA-DR molecules expressed by B cells and monocytes. Moreover, when TNP-modified, the irradiated cloned T cells functioned very effectively to stimulate TNP-specific proliferation by cloned responders; when unmodified they were potent stimulators of allogeneic mixed leukocyte responses. Thus, for haptens covalently attached to cell membrane proteins and for allogeneic HLA antigens, Ia⁺ cloned T cells can function as effectively for antigen presentation and T cell activation as other Ia⁺ populations to which such properties have been ascribed.     

Synovial biology and T cells in rheumatoid arthritis.

Events that occur in rheumatoid arthritis synovial tissues are responsible for the signs and symptoms of joint inflammation and for the eventual destruction of articular and periarticular structures that lead to joint dysfunction and disability. The three most abundant cell populations in RA synovium are synovial macrophages (type A synoviocytes), synovial fibroblasts (type B synoviocytes) and infiltrating T lymphocytes. Other important cell populations include B lymphocytes, dendritic cells, plasma cells, mast cells and osteoclasts. Our current understanding of rheumatoid arthritis is moving beyond previous concepts that view this disease as the consequence of a specific and focused humoral or cellular autoimmune response to a single autoantigen. Rather, a new view of rheumatoid arthritis is emerging, which seeks to understand this disease as the product of pathologic cell-cell interactions occurring within a unique and defined environment, the synovium. T lymphocytes in rheumatoid arthritis synovium interact closely with dendritic cells, the most potent antigen-presenting cell population in the immune system. T cells also interact with monocytes and macrophages and cytokine-activated T cells may be, especially, suited to trigger production of the important cytokine TNFalpha by synovial macrophages. Recent evidence also suggests a potent bidirectional interaction between synovial T cells and synovial fibroblasts, which can lead to activation of both cell types. An important role for synovial B lymphocytes has been emphasized recently, both by experimental data and by results of clinical interventions. B cells in synovium can interact with fibroblasts as well as with other cells of the immune system and their potential role as antigen-presenting cells in the joint is as yet underexplored. Rheumatoid arthritis synovium may be one of the most striking examples of pathologic, organ-specific interactions between immune system cells and resident tissue cell populations. This view of rheumatoid arthritis also leads to the prediction that novel approaches to treatment will more logically target the intercellular communication systems that maintain such interactions, rather than attempt to ablate a single cell population.     

Boosting antibody responses by targeting antigens to dendritic cells

Delivering antigens directly to dendritic cells (DCs) in situ, by injecting antigens coupled to antibodies specific for DC surface molecules, is a promising strategy for enhancing vaccine efficacy. Enhanced cytotoxic T cell responses are obtained if an adjuvant is co-administered to activate the DC. Such DC targeting is also effective at enhancing humoral immunity, via the generation of T follicular helper cells. Depending on the DC surface molecule targeted, antibody production can be enhanced even in the absence of adjuvants. In the case of Clec9A as the DC surface target, enhanced antibody production is a consequence of the DC-restricted expression of the target molecule. Few other cells absorb the antigen-antibody construct, therefore, it persists in the bloodstream, allowing sustained antigen presentation, even by non-activated DCs.     

Interactions between epithelial cells and T lymphocytes: role of adhesion molecules

Cell-cell interaction is critical for normal T cell development and function. A number of adhesion molecules important in T cell interactions with other cell types have been defined. This paper reviews the role of two adhesion pathways, CD2/LFA-3 and LFA-1/ICAM-1, in T cell interactions with epithelial cells of the thymus and skin. While thymic epithelium-T cell interactions are mediated by both the LFA-1/ICAM-1 pathway and the CD2/LFA-3 pathway, epidermal-T cell interactions are mediated primarily by the LFA-1/ICAM-1 pathway. Although ICAM-1 is not expressed in vivo on epidermal keratinocytes in normal skin, ICAM-1 is expressed by epidermal keratinocytes at the site of T cell infiltration in inflammatory dermatitis. ICAM-1 is expressed in vivo on thymic epithelium. These antigen independent adhesion molecules play an important role in the cell-cell interactions associated with T cell differentiation and function.     

Genetic aspects of cellular interactions in the immune response

Our understanding of the complex cellular interactions responsible for mediating effective immune responses has increased substantially in recent years. It is now clear that the genetic loci that control the interaction of the cells of the immune response encode groups of closely related cell-surface molecules. These molecules are the class I and class II antigens of the MHC, the differentiation antigens on lymphocyte subpopulations, and the receptors of various types, including the membrane immunoglobulin of B lymphocytes and the antigen receptors of T lymphocytes. Biochemical analysis of these cell surface molecules has demonstrated that they display important DNA sequence homologies. A polypeptide of approximately 110 amino acids comprises the basic building block for many of the cell surface molecules. Gradually, as a consequence of evolutionary development, the immune system has expanded its ability to respond to the external environment by an increased complexity of lymphocyte subpopulations and the surface structures that modulate their interaction. These cell surface molecules provide the structures that allow collaborative interaction of different cell types and that form the multiprotein receptor complexes involved in the recognition of, and specific response to, foreign antigens. Our future understanding of the control of the immune response will depend upon establishing the biochemical nature and the multifaceted interactions of these important molecules.     

Antigen presenting cells integrate opposing signals from CD4+ and CD8+ regulatory T lymphocytes to arbitrate the outcomes of immune responses.

An individual's set of polymorphic HLA class II and I molecules is known to select the T cell repertoire in the thymus and to present processed antigenic peptides (pAg) to mature peripheral CD4+ T helper (Th) and CD8+ T cytotoxic (Th) cells in the periphery. This review highlights new studies which address how antigen presenting cells (APC) integrate the responses of cognate Th and T suppressor (Ts) cells to determine the outcome of immune responses. Together with other findings, these studies emphasize that understanding the mechanism of immune processes requires consideration of HLA molecules in the context of the peptides they bind, the antigen presenting cells (APC) that express them and the T lymphocytes that recognize them. The activities of lymphocyte and APC surface structures are becoming integrated into a physiological understanding of the cellular interactions between regulatory and effector T cells with APC.     

Interactions of T lymphocytes with human vascular endothelial cells: role of endothelial cells surface antigens

We have studied the interactions of peripheral blood T lymphocytes with cultured human vascular endothelial cells, focusing upon endothelial cell surface antigens important for T cell recognition. Under standard culture conditions endothelial cells express class I but not class II major histocompatibility complex (MHC) antigens. However, class II antigens may be induced by activated T cells or T cell products, including the lymphokine immune interferon. Immune interferon concomitantly increases class I antigen expression and causes a change in cell shape. In addition to vascular endothelial cells, we have found that vascular smooth muscle cells and human dermal fibroblasts may also be induced by immune interferon to express class II antigens. All known human class II antigens are induced (i.e. HLA-DR, DC and SB) as is the associated invariant chain. Induced antigen expression in these cells is stable over several days, although mRNA levels decline rapidly upon withdrawal of interferon. Vascular and stromal cell class II antigens are functional, in that they can be recognized by cytolytic and helper T cell clones. Several non-MHC antigens are also involved in the recognition of endothelial and stromal cells by T cells. We propose a model for the role of inducible class II molecules on endothelium and stromal cells in vivo: The induction of class II MHC antigens on endothelial cells, locally mediated by activated T cells, enables endothelium to present an immunogenic cell surface structure, comprised of antigen plus self class II polymorphic determinants, which in turn, serves to recruit additional antigen-specific T cells from the circulation into the site of a developing cell mediated immune response. Class II molecules on stromal cells, also induced locally at the site of a developing response, confers immune accessory function on these cells and may serve to augment and sustain a T cell response.     

Autologous apoptotic T cells interact with dendritic cells,but do not affect their surface phenotype or their ability to induce recall immune responses

Dendritic cells (DCs) play an important role in determining immunogenicity and the subsequent immune response. They may also have a role in maintaining peripheral tolerance to self-antigens by initiating an immune response only in the context of danger signals released from cells during stress, damage or death. These signals may originate from surrounding T cells as well as from other cells. Therefore, in this study the effect of autologous T cell injury on DC morphology and function has been investigated. Co-incubation of apoptotic or necrotic T cells with immature DCs altered their morphology towards a more mature appearance, with more cells showing activation as judged by spreading and formation of arborizing long processes. The apoptotic autologous T cells were rarely phagocytosed by immature DCs, compared to macrophages. The DC surface phenotype was not affected by the co-incubation with autologous injured T cells. The ability of DCs to elicit a secondary immune response was not altered by exposure to autologous injured T cells. These findings suggest that DC can continue to function in T cell activation, rather than in tolerogenic mode, even in the presence of large numbers of dying autologous T cells, such as may be present in the aftermath of an acute antiviral response.     

T follicular helper cells in cancer,tertiary lymphoid structures,and beyond

With the emergence and success of checkpoint blockade immunotherapy, immuno-oncology has primarily focused on CD8 T cells, whose cytotoxic programs directly target tumor cells. However, the limited response rate of current immunotherapy regimens has prompted investigation into other types of tumor-infiltrating immune cells, such as CD4 T cells and B cells, and how they interact with CD8 T cells in a coordinated network. Recent studies have demonstrated the potential therapeutic benefits of CD4 T follicular helper (TFH) cells and B cells in cancer, highlighting the important role of their crosstalk and interactions with other immune cell components in the tumor microenvironment. These interactions also occur in tumor-associated tertiary lymphoid structures (TLS), which resemble secondary lymphoid organs (SLOs) with orchestrated vascular, chemokine, and cellular infrastructures that support the developmental pathways of functional immune cells. In this review, we discuss recent breakthroughs on TFH biology and T cell-B cell interactions in tumor immunology, and their potential as novel therapeutic targets to advance cancer treatment.     

Multiple survival signals are delivered by dendritic cells to naive CD4+ T cells

The molecular mechanisms by which dendritic cells (DC) favor naive T cell survival in mice have been examined in co-cultures of DC and naive CD4+ T cells. Naive T cells can survive in the presence of IL-4 or IL-7, but DC-induced T cell survival requires direct cell-cell interactions and does not seem to be mediated by these or other soluble factors. Classical MHC II molecules on DC are not necessary for T cell survival as long as hybrid AalphaEbeta MHC class II molecules are present. In the total absence of MHC II molecules on DC, T cell survival is reduced by half, and CD3zeta phosphorylation fully disappears. These results contrast with the classical view that naive T cell survival is associated with CD3zeta phosphorylation and depends mostly on IL-7 and MHC-TCR interactions. We demonstrate that DC-induced T cell survival is a multi-factorial process that also involves CD28, LFA-1 and another (as yet undefined) surface molecule that requires the activity of src (but not phosphatidylinositol-3-) kinase.     

MHC transfer from APC to T cells following antigen recognition

Recognition of cognate MHC:peptide complexes by T cells leads to large-scale molecular rearrangements resulting in immunological synapse formation at the T cell-antigen-presenting cell (APC) interface. Although the functions of the immunological synapse are not completely understood, a consequence of this event appears to be the intercellular transfer of MHC:peptide complexes, along with other molecules such as CD80, from the APC to the T cell. The expression of APC-derived molecules on the T cell is biologically significant. It has the potential to alter the homing, allow T cells to also act as APC, and may alter the effector functions of the cell. Experimental evidence suggests that intercellular transfer may play a role in the control of an immune response; however, the exact role is unclear. Both potentiation and attenuation of an ongoing response have been postulated. In addition, removal of molecules from APC may be important in controlling homeostatic proliferation, in affinity maturation of T cells, and in maintaining epitope diversity during an immune response. In this review, we highlight recent advances regarding the mechanism of intercellular transfer and focus on the potential biological significance of this event.     

Immunodeficiency virus exploitation of dendritic cells in the early steps of infection

The unique capacity of dendritic cells (DCs) to capture and process pathogens for presentation to the immune system, combined with their capacity to express costimulatory and adhesion molecules as well as cytokines and chemokines, renders them powerful antigen-presenting cells. However, immunodeficiency viruses hijack DCs to facilitate virus dissemination while subverting effective immune activation. Depending on the activation level of the DC subset, human immunodeficiency virus can use different receptors (CD4, chemokine, and C-type lectin receptors) to bind to DCs. These aspects likely impact whether a DC is productively infected by or simply carries virus for transmission to more permissive targets. DCs efficiently transmit virus to CD4+ T cells, driving virus growth as well as providing signals to trigger virus expansion in virus-bearing CD4+ T cells. There is accumulating evidence that viral determinants (nef, tat) selectively modulate immature DC biology, fostering DC-T cell interactions and virus replication without up-regulating costimulatory molecules for effective immune function. In addition, virus-loaded, immature DCs activate CD4+ virus-specific T cells, and mature DCs stimulate CD4+ and CD8+ T cells. Thus, even if immature DCs entrap virus as it crosses the mucosae and initiate a CD4+ T cell response, this is likely insufficient to control infection. Appreciating how virus modulates DC function and what determines whether virus is processed for immune stimulation or transmitted between cells will unveil the exact role of these cells in the onset of infection and advance preventative microbicide and vaccine/therapeutic approaches.     

Activating interactions in human NK cell recognition: the role of 2B4-CD48.

2B4 is a cell surface glycoprotein of the immunoglobulin superfamily structurally related to CD2-like molecules. It was originally identified in the mouse as a receptor that mediates non-MHC-restricted cytotoxicity by NK cells and CD8+ T cells. Recently, 2B4 was shown to bind CD48 by molecular binding assays and surface plasmon resonance. Here, we have investigated the cell surface expression, biochemical characteristics and function of human 2B4. Our results show that 2B4 is expressed not only on NK cells and CD8+ T cells, but also on monocytes and basophils, indicating a broader role for 2B4 in leukocyte activation. In NK cells, engagement of 2B4 with a specific monoclonal antibody or with CD48 can trigger NK cell-mediated cytotoxicity. The contribution of 2B4-CD48 interaction to target cell lysis by different NK cell clones varies, probably dependent on the relative contribution of other receptor-ligand interactions. In T cells and monocytes, ligation of 2B4 does not lead to T cell or monocyte activation. Thus, it appears that the primary function of 2B4 is to modulate other receptor-ligand interactions to enhance leukocyte activation.     

MHC class I molecules, structure and function

MHC class I molecules (MHC-I) are cell surface recognition elements expressed on virtually all somatic cells. These molecules sample peptides generated within the cell and signal the cell's physiological state to effector cells of the immune system, both T lymphocytes and natural killer (NK) cells. In addition, molecules structurally related to MHC-I, collectively known as MHC-Ib, are more specialized and, in some cases, interact with more limited subsets of lymphoid cells. Using the recently determined structure of the classical MHC-I molecule, H-2Dd, as a paradigm for structure and function, we review other MHC-I and MHC-Ib molecules, with an emphasis on how the same basic structural fold is employed by classical MHC-I molecules to bind specific peptides and T cell receptors, and is exploited by the MHC-Ib molecules in more stringent molecular interactions. It is instructive that structurally related molecules have evolved to perform a number of unique and distinct functions in immune and non-immune recognition.     

Dendritic cells in the initiation of immune responses against central nervous system-derived antigens

Antigen presentation is essential for the activation and maintenance of antigen-specific T cell responses in the nervous tissue. Generally, it is becoming well accepted that the antigen presenting cell (APC) type responsible for the initiation of the primary immune response through the exclusive ability to activate na?ve T cells is the dendritic cell (DC); however, the role of these cells in central nervous system (CNS) immunity is unclear at this time. The diverse phenotypes and origins of DCs make the characterization of their function in the CNS even more difficult. It is believed that DCs can influence the immune response in several ways: these cells are not only capable of initiating the immune response but they are also a major determinant of peripheral tolerance. DCs are characterized by the constitutive ability to express MHC class II molecules as well as high-level upregulation of these molecules in response to inflammatory stimuli. A pan DC marker that has proved to be useful in identifying them is CD11c (the alpha-chain of CR4); other markers include CD205 and MHC class II. DCs also actively participate in the humoral immune response. In this review, we would like to discuss how DCs appear in the CNS and their roles in initiation, maintenance and tolerance in the immune reactions in the CNS.     

Role of gp120 in dendritic cell dysfunction in HIV infection

Only a limited fraction of circulating virions are demonstrably infectious; therefore, exposure to inactivated viruses may mimic the most frequent type of CD4-HIV interactions that occur in vivo. Several studies have recently underscored the crucial role that those noninfectious viruses could play in defective immune function in HIV-infected individuals and in particular, in the dysregulation of dendritic cell (DC) function. In this review, we discuss how interactions between DC and HIV gp120 or inactivated virus, which harbor intact surface gp120, lead to impaired DC function through direct (direct contact) or indirect mechanisms (as a consequence of primary CD4+ T cell dysregulation, followed by defective CD4-DC interactions). It is important that these functionally impaired DCs fail to give optimal signal to T cells but appear to favor the emergence of regulatory T cells. gp120-mediated impairment of DC function could therefore play an important role in the pathogenesis of HIV disease.