The role of dendritic cells in T cell activation - Nature

Immunology and Cell Biology (1997) 75. 223-230

Review Article

The role of dendritic cells in T cell activation K NI and HC O'NEILL Division of Biochemisliy and Molecular Biology, Faculty of Science. Australian National University, Australian Capital Territoi-y. Australia

Canberra,

Summary Dendritic cells (DC) are distinguishable from other antigen-presenting cells hy their potent antigen-presenting capacity. They are not only efficient at presenting peptide antigen but can also process and present soluble protein antigens to antigen-specific T cells and cloned T cell lines. They are very strong stimulators of both allogeneic and syngeneic mixed lymphocyte reactions and have a unique capacity to stimulate naive T cells. The potent functional capacity of DC is related to a high-level expression of major histocompatibility complex class IAI molecules and constitutive expression of costimulatory molecules, such as CDS0/CDS6. as well as heat stable antigen. CD4n and the leucocyte function antigen (LFA) family of adhesion molecules. Recent studies have shov^n that DC are also involved m regulation of the immune response via induction of both central and peripheral tolerance. Key words: antigen presentation capacity, costimulators. dendritic cells. T cell activation, tolerance.

Introduction Dendritic cells (DC) are involved in many aspects of T cell function. They provide accessory cell function required for mitogenic responses in T lymphocytes'- and antigenic stimulation.^ They act as potent stimulators of a mixed lymphocyte reaction (MLR),"'-'' induce antigen-specifie antibody responses in vivo'' and serve as critical passenger cells which elicit rejection of transplanted tissues.^ They are distinguishable from other antigen-presenting cells (APC) by their typical morphology and unique functional effectiveness in T lymphocyte activation. Dendritic cells constitutively express high levels of both major histocompatibility complex (MHC) class I/II and eostimulatory molecules and have been shown to be superior APC, capable of activating naive T cells.'*'* In fact, it has been proposed that DC are the only APC which can prime naive T cells.'" In contrast, macrophages (M0) and B cells are APC for only memory or activated T cells, although this is still a matter of debate.""'^

T cell stimulatory capacity of DC The MLR is an in vitro correlate of cell-mediated Immune function'* and can be used as a final test for tissue eompatibility, for example, in bone marrow transplantation. The elinical relevance of this assay has been based on the assumption that donor lymphocytes carry all alloantigens of the organ to be grafted. However, some non-lymphoid organs, including skin, liver, heart, kidney, and vascular endothelium also contain cells that can stimulate an allogeneie lymphocyte population.'^ This type of work has indicated a role for specialized APC including DC in these tissues."' Correspondence: Dr HC O'Neill, Divisii)n of BitKhemistry and Molecular Biology. Faculty of Science. Australian National Universily. Canberra, ACT 2601, Australia. Received 29 Ociobcr 1996; accepted 10 February 1997.

Dendritic cells are unique in their capacity to stimulate both syngeneie and allogeneic MLR as well as present antigen to naive T cells. They ean also stimulate a CTL response. After a single in vitro stimulation. DC eells can induce proliferatiiin of virus-specific CTL either by presenting viral peptide or processing antigens of infectious virus.'^ Primary CTL activity was blocked by antibodies specific for leucocyte function antigen (LFA)-1 or CDS. indicating that appropriate T cell co-receptors are involved in the stimulation event.'^ Anti-Ig activated B cell blasts were found to be 3-10-fold less active than DC in a primary allogeneie MLR. although they were equal or more active on a per cell basis in a secondar>' MLR.'^ Macrophages and granulocytes are unable to act as APC for a syngeneic MLR. Only mature DC and activated B eells ;u-e effective in this response,'"*-" B eells being weaker than DC.'^ Evidence that the syngeneic MLR response is much stronger in the presence of 59( FCS than in 2.5^'c isologous serum.-" indicates a possible role for environmental antigens such as xenogeneie serum proteins. There is evidence that FCS used in medium, or factors released from cultured B lymphoid leukaemia eells. can be presented as a soluble antigen for T cell stimulation, providing an explanation for autologous lymphocyte stimulation.-' Other studies have shown the opposite, that FCS-derived antigen plays no role in the capacity of cultured eells to stimulate T cells.-' While DC are known to specifically induce an autologous MLR. the nature of any antigen involved is still unknown. Physical contact between the T cell and APC is required for the induction of T cell stimulation. Thymic rosettes, consisting of 3-30 thymic lymphoid eells, attached to a central Mo or DC have been shown to exist as a cell cluster within thymus. These are also subject to extensive exchange with free thymocytes under certain conditions. Furthermore, each of the established thymic subpopulations defined by CD4 and CDS have been shown to be involved in clustering with DC.^-

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This function has beeti associated with mature DC as freshly isolated DC and Langerhans cells (LC) only weakly cluster with T cells. Tliis activity can be up-regulated by culture of the cells with granulocyte/macrophage colony-stimulating factor (GM-CSF).--^-'' Cluster formation between DC and T cells can be inhibited by a number of mAb specific for cell surface molecules associated with T cell activation. These include antibodies specific for LFA-l(M17/5.2)--'' and Fc receptor (FcR)(2.4G2).-^ Activation of CD4"^ T cells is a multistep process which involves the uptake and processing of protein antigens and the subsequent presentation of immunodominant peptides by MHC class II molecules on the surface of APC.-^ In the case where highly puriHed H-2^-positive mouse spleen DC present hen egg-white lysozyme {HEL)-derived peptide to an l-A'' restricted T hybridoma cell line specific for HEL peptide 4661, these DC were 100 titnes more efficient than LPS-mduced B cell blasts.'^ Treatment of DC with chloroquine, a weak base that neutralizes acidic organelles,-^ was shown to inhibit capacity of HEL-pulsed DC to present tbe HEL antigen to T cells. This indicates that antigen processing involving endocytosis and acidic cell compartments is necessary for MHC class II restricted antigen presentation. The DC supernatant was also found to contain the immunogcnic peptide fragment.'^ Dendritic cells are very efficient at endocytosis and presentation of complex soluble antigens such as HEL. Microparticle-absorbed protein antigen can be taken up by bone marrow-derived DC. Use of this form of antigen augments antigen-presenting capacity and maintains the antigen within the cellular environment.-^'' Phagocytosis of particle-absorbed protein by progenitor DC involves an activation event, with synthesis of interleukins IL-la and IL-12. In comparison with M0, most MHC class IT mature DC are weak or not phagocytic for particle-absorbed protein,-'' while LC and precursors of DC have been shown to be very phagocytic.'"•''' All these data indicate that DC not only present peptide fragments to T cells, but arc also able to endocytose and process particulate and soluble protein antigen, and immature DC are superior to mature DC in both endocytosis of soluble antigen^- and phagocytosis.

Two signal model of T cell activation Activation of T cells through the TCR in the absence of accessoiy cells leads to both suboptimal proliferation and lymphokine production.''^ Evidence that specialized costimulatory signals produced by APC were needed for efficient T cell activation was first obtained in the allograft rejection model, whereby elimination of APC from an allograft resulted in graft survival."" By this model, optimal T cell activation was shown to require two signals provided by the APC; signal I originates from the peptide-MHC/TCR interaction. This can also be mimicked by superantigens and antibodies to TCR. Signal 2 provides the costimulatory signal(s). This can be mediated through one or more costimulatory molecules. The nature and quantity of signal 2 determines the outcome of T cell activation and is likely to vary with the T cell population being studied. Recent evidence has shown that the costimulator B7(CD80/CD86) and MHC-peptide complexes need to be

expressed on the same cell for optimal T eel! activation.^* That human LC express 50-100-fold more HLA-DR than M& and blood DC, is consistent with evidence that LC are more efficient APC than some DC isolates, and that the antigenpresenting capacity of DC in different organs may vary. This could be a result of variation in the expression of costimulator (B7) or MHC on DC in different sites. The requirement for costimulation via the CD28-B7 interaction is lost if T cells have already been activated.-^^-^^ Some CD45RO* memory T cells, however, can be activated in vitro by remote CD80/CD86(B7)" or by CD80/CD86(B7) expres.sed on bystander cells.-^'^ Costimulation in vivo can also be provided by bystander cells.-^^ Dendritic cells are the most potent accessory cells for stimulation of antigen-specific T cells, using either soluble or paiiiculate antigen."**^ However, individual clones of T cells have a different capacity to respond to antigen presented on either DC or Mo. Possible synergy between the two accessory cell types in immune response development has not, so far. been demonstrated. While uncloned T cell lines may be induced to proliferate by a variety of APC types, T cells differ clonally in their requirement for antigen and costimulation for activation.'*'^' This suggests that one variable in the stimulation of a T cell clone is the type of APC by which antigen is presented/" Dendritic cells may not be able to effectively process all protein antigens and this could relate to the size and secondary structure of the molecule. It has been shown that Mo, but not DC or B cells, are the primary APC in the immune response towards type II collagen."""'- As DC can present other peptides and proteins such as ovalbumin, pepsin or myelin basic protein to T cells, this deficiency in antigenpresenting capacity would not appear to reflect a failure of DC to take up or process this particular protein antigen."^' The ability of DC to process and present protein antigens is also known to be dependent on the strain of otigin of mouse DC. For example. LC from /d* mice are able to present intact protein to antigen-specific T cells, while LC from la'' mice are not.*"' CD4+ T cells can be classified into T helper cell type (Th)l and Th2 by their eytokine profile and can be distinguished functionally by the production of IFN-y and IL-4, respectively. Appropriate commitment of developing T cells to Thl or Th2 type during an immune response to a pathogen, allergen or auto-antigen, may determine the difference between health and disease. Dendritic cells produce IL-12 which preferentially directs the development of naive CD4+ T cells into the Th 1 type."*^"*^ Normally, costimulation via B7-CD28 interaction is sufficient to induce significant proliferation of naive T cells, but IL-12 is required for potent stimulation of some Thl clones, which arc unresponsive to B7 costimulation.'*^^'* Synergistic interaction between B7-CD28 costimulation and IL-12 is much stronger than the interaction of B7-CD28 with IL-2.-''^--'^" The production of IL-12 by DC can be up-regulated by various means, such as overnight culture,^' LPS''\ or upon bacterial stimulation and interaction with T cells""^ involving CD40 and CD40L.-'^-'^^ However, the production of IL-12 by DC which directs naive T cells towards Thl development is not universal, as some DC preparations produce insufficient IL-12 and are poor at inducing proliferation of Thl

Role of DC in T cell activation

.**^"*^ This may reflect DC al different stages of development or the presence of DC with a different functional capacity in different tissue.^"* IL-12 induces high IFN-y production in naive T ceils which subsequently results in skewing of cytokine production towards a Thi lype.-'^-'*--'^' Recently it was shown that IFN-y can significantly augment IL-12 production of subsequent IFN-7 production by T cells, while IFN-7 alone can not induce Thi development. It seems, however, that IFN-y provides a direct signal to T cells to up-regulate IL-12-induced Thi development.-*^^

Costimulatory molecules involved in T cell activation by dendritic cells Optimal activation of T cells requires multiple signalling events. These include costimulator-ligand interactions-'*'^ and soluble factors such as lL-1. IL-6 and IL-i2.^"'^''' The number of costimulator molecules now described is expanding rapidly. The CD28 molecule, present on thymocytes and most mature resting T cells^-"^ is an important T cell regulatory molecule. B7 or its B7-I''''-^^ form is a natural ligand for CD28. and interaction between CD2S and B7 can mediate T-B cell adhesion.''-^*' Evidence indicating that B7 participates in T cell stimulation was first shown by Azuma el al. in 1992.3^ B7 transmits a signal through the CD28 receptor on resting T cells, but transmits through multiple receptors CD28 and cytotoxic T lymphocyte antigen (CTLA)-4 on activated T cells.''- ln 1993. a new member of the B7 lamily. namely B7-2, was found to be expressed constitutively on human DC, but to vary in expression on B cells. It was also shown to be expressed by mature LC and activated or resting monocytes.^*^™ It functions to costimulate naive T cells responding to alloantigen.^' Evidence to date now demonstrates that the B7 tamily comprises important costimulatory molecules^^^*-'^-''^-^-^ expressed on murine DC,^- peritoneal exudate cells.^^ and M0.^"*-^-'' These molecules are also expressed after repeated activation of human T cells, or by T cells activated with either superanligen or specific antigen in the presence of IL-2.'''' B7 expression is also up-rcgulated on LC during maturation''^''- and this is known to take place at the RNA level.'^ Recent evidence now indicates that the expression of B7-I/B7-2'^ is not always an indicator of functional capacity of APC in T cell stimulation. The resting DC population isolated by immunodepletion of lineage positive cells from human peripheral blood is B7-2'""'. B7-l-."'» After brief culture for 24 hours //( vitro, cells become B7-1*, 87-2*"*". Granulocyte/macrophage colony-stimulating factor up-regulates both B7-1 and B7-2 expression on DC. while IFN-y upregulates only B7-2.^'' However, only GM-CSF can upreguiate DC immunostimulatory function in an allogeneic MLR.^"^ B7-2 is both the earliest and the most functionally predominant ligand for CD28 or CTLA-4 on DC. Cell surface expression of B7-2 is detectable on LC within 8 hours of culture, whereas B7-1 is not present until 24 hours of culture. CTLA4-Ig and anti-CD86 (B7-2) but not anti-CD80 (B7-1) mAb can block an ailogeneic MLR stimulated by DC.^*^ However, adherent monocytes, which express B7-2, are

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unable to induce T cell proliferation in response to recail antigen and fail to induce naive T cell responses to protein anligen.**" B7 may be a necessary costimulator but msufficient when expressed on monocytes to give effective stimulation of T cells. The question of what makes DC a more effective APC remains to be addressed. Leucocyte function antigen-1 has at least three counter receptors, ICAM-1, ICAM-2 and lCAM-3.«i*«^ Both ICAMI and ICAM-2 can function as costimulators of anti-TCR-a(i or anti-CD3 antibody-driven proliferation of CD4^ T ceils.'***^'" However, proliferation of resting T cells is more dependent on stimulation provided by ICAM-1 than by ICAM-2 or B7.'*^ Antigen-primed CD4'' T cells are most efficiently costimuiated by B7 and weakly by either ICAM-1 or lCAM-2.^'' Leucocyte function antigen-1 receptor-ligand interaction may be involved in APC-T cell clustering as a tirst step in T cell-APC interaction. Antibodies against LFA-1 and ICAM-1 can inhibit T cell-APC interaction in a primar>' allogeneic MLR^*^ in a dose-dependent manner.'"' Expression of ICAM-1 is also required for rejection oi B7-Itran.sfected tumour cells and the establishment of a memory response in vivo.^^ The murine heat stable antigen (HSA). which is closely associated with specilic stages of intrathymic T cell development,"** has also been identified as a costimulator. Heat stable antigen is expressed by some LC and DC isolates.'*'' The function of HSA was unknown until Liu ci al. identified it as a costimulator involved in murine CD4* T cell activation by activated B cells.'"'"' The costimuiatory function of HSA has now been demonstrated for both LC"-'" and DC.*"' and both B7 and HSA were shown to cooperate in promoting T cell proliferation."" Blocking of either B7 or HSA alone with antibody can inhibit T cell proliferation by up to 90'/^. A combination of these antibodies has also been shown to inhibit clonal expansion of CD4* T cells. There have been other reports of costimulatory function associated with CD40,"^''-'' which is also expressed by DC/LC."•''"' Although some molecules such as ICAM-l/LFA-1 and HSA are important adhesion and costimulatory molecules, their distribution on a variety of cell types indicates that cell surface expression of these molecules alone does not account for the unique ability of DC and blast cells to activate resting T celis,''' Clearly the process of costimulation appears to involve multiple receptor-ligand interactions, and these could vary qualitatively and quantitatively dependent on the type of APC and T cells which interact. There is not a clear dependency on one costimulator type as there is for the TCR-antigcn/MHC interaction.

The role of dendritic cells in tolerance induction Increasing evidence now indicates a regulatory role for DC in tolerance induction. In the thymus, selt-tolerance occurs by deletion of self-reactive T cells. Dendritic cells play a roie by interacting with developing T cells in the thymic environment during negative selection. Experimental work in vivo has shown that intrathymic DC can present circulating soluble non-MHC antigen to T cells.''" Intravenous injection of an enriched population of thymic DC pulsed with encephalogenic peptide of niyelin basic protein (MBP) can prevent the

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development of experimental autoimmune encephalomyelitis. Protection is similar to that invoked by direct intrathymic inoculation of MBP.^'* This protection is lost in thymectomized recipients, emphasizing the important role of the thymic environment in the induction of tolerance. Intrathymic injection of M/i-incompatible spleen or thymic DC can induce tolerance via clonal anergy.'^*^' The ability of DC to induce tolerance is not restricted to thymic DC and a critical role for peripheral DC in central tolerance has been demonstrated by the restoration of tolerogenic properties of APCdepleted thymi using purified spleen DC."^^ Dendritic cells can also induce peripheral tolerance. Intravenous administration of antigen-pulsed LC or spleen DC into syngeneic mice can also induce antigen-specitic suppression of a delayed-type hypersensitivity (DTH) response to challenge ofthe ear with the same antigen,'^'^•'"•'^ Coculture of bone marrow-derived DC progenitors with naive T cells in vitro induce alloantigen-specific hyporesponsiveness, and systemic administration of these DC progenitors into allogeneic mice can prolong the survival of heart or pancreatic islet allografts in vivo.''^"^^ The identification of a unique subset of thymic and splenic DC, which express CD8 and induce apoptosis in activated T cells by Fas-FasL interaction, emphasizes the existence of extensive phenotypic and functional heterogeneity among DC in v/vo."^'^"^'' The nature of antigen presentation or other factors associated with the antigenic environment determine whether DC can induce tolerance or responsiveness. Very recently. Finkelman et al. observed that DC can present antigen in either a tolerogenic or immunogenic fashion depending on the inoculation regimen used."^'^ It was found that the injection of mice with a rat-IgG2b anti-spleen DC antibody 33D1 induced rat TgG2b-specific T and B cell tolerance. In contrast, injection of mice with aggregated 33DI, 33D] plus anti-IgD mAb, or 33D1 plus IL-1 induces an IgGl anti-rat IgG2b response rather than tolerance.

DC differentiation from precursors.''^ 1L-1"° and IL-4'>' can synergize with GM-CSF to further enhance the T cell-stimulating capacity of DC. Tumour necrosis factor {TNF)-a can effect DC maturation in vitro in a manner different from GM-CSF by reducing DC capacity to process and/or present protein."^ It acts to induce migration of tissue DC from nonlymphoid sites into secondary lymphoid organs"''"'' in a process of in vivo maturation."^ The role of IFN-7 in the induction of DC maturation is controversial. Treatment of DC with IFN-7 increased their capacity to stimulate antigenspecific and naive T cells,"^ "'' lFN-y increased the expression of B7-2 on DC lines but did not increase their stimulation capacity.^^ Cross-linking CD40 on DC with soluble CD40L can also increase the APC function of DC, evident by augmented T cell stimulation activity and increased DC expression of MHC class lAl, B7 and ICAM.'*^-^^'"^ Terminal maturation of DC occurs during interaction with T cells, leading to the up-regulation of CD40 expression.**^ These observations suggest that a mutual activation mechanism occurs between T cells and DC upon their interaction. Conclusion Many studies have been carried out on the function of DC in different arms of the immune response. It is widely accepted that DC are the most important APC for priming naive T cells, activating antigen-specific T cells and inducing thymic tolerance. Studies using well-defined DC subpopulations from various tissue sites or DC at different developmental stages should provide a clear understanding of the diverse role of DC in immune responses. It is also important to address the role of costimulator molecules in T cell activation since these are not universally expressed by all DC types. Different DC subsets with different costimulatory capacity and at different stages of development provide diversity in immune response potential.

Functional maturation of dendritic cells Dendritic cells undergo a maturation process after antigen challenge in vivo or following short-term in vitro culture. Immature DC are highly effective at processing foreign protein antigens but can only weakly cluster T cells or stimulate resting T cells.-^•-•* During the process of maturation, DC increase in size and T cell-stimulating capacity, and express increased levels of cell surface antigens important in T cell activation, such as MHC class lfll B7. ICAM-1. LFA-3, and CD40. In the mature state they efficiently stimulate resting antigen-specific T cells. Dendritic cells in non-lymphoid sites are immature. From here they migrate via afferent lymphatics or the blood to the T cell-dependent areas of the lymphoid organs (lymph node and spleen), where they function as mature DC. Langerhans cells in epidermis represent immature tissue DC and, after 2-3 days in culture, they develop the characteristics of mature DC."^^ Maturation of DC can be induced by cytokines. Cell culture-conditioned medium was first shown to induce human blood immature DC to express typical dendritic features and potent T cell-stimulating capacity. Granulocyte/macrophage colony-stimulating factor has smce been shown to be the cytokine effective in mediating DC maturation and to induce

Acknowledgement This work was supported by a grant from the Clive and Vera Ramaciotti Foundation of Australia.

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