Dendritic cells (DCs) have several functions in innate and adaptive immunity. In addition, there is increasing evidence that DCs in situ induce antigen-specific unresponsiveness or tolerance in central lymphoid organs and in the periphery. In the thymus DCs generate tolerance by deleting self-reactive T cells. In peripheral lymphoid organs DCs also induce tolerance to antigens captured by receptors that mediate efficient uptake of proteins and dying cells. Uptake by these receptors leads to the constitutive presentation of antigens on major histocompatibility complex (MHC) class I and II products. In the steady state the targeting of DC antigen capture receptors with low doses of antigens leads to deletion of the corresponding T cells and unresponsiveness to antigenic rechallenge with strong adjuvants. In contrast, if a stimulus for DC maturation is coadministered with the antigen, the mice develop immunity, including interferon-gamma-secreting effector T cells and memory T cells. There is also new evidence that DCs can contribute to the expansion and differentiation of T cells that regulate or suppress other immune T cells. One possibility is that distinct developmental stages and subsets of DCs and T cells can account for the different pathways to peripheral tolerance, such as deletion or suppression. We suggest that several clinical situations, including autoimmunity and certain infectious diseases, can be influenced by the antigen-specific tolerogenic role of DCs.

https://digitalcommons.rockefeller.edu/cgi/viewcontent.cgi?article=1153&context=steinman-publications

Tolerogenic dendritic cells.

Great progress has been made in the field of tumor immunology in the past decade, but optimism about the clinical application of currently available cancer vaccine approaches is based more on surrogate endpoints than on clinical tumor regression. In our cancer vaccine trials of 440 patients, the objective response rate was low (2.6%), and comparable to the results obtained by others. We consider here results in cancer vaccine trials and highlight alternate strategies that mediate cancer regression in preclinical and clinical models.

/pdf/cancer-immunotherapy-moving-beyond-current-vaccines-37qufn3ryj.pdf

Cancer immunotherapy: moving beyond current vaccines.

Dendritic cells (DCs) orchestrate a repertoire of immune responses that bring about resistance to infection and silencing or tolerance to self. In the settings of infection and cancer, microbes and tumours can exploit DCs to evade immunity, but DCs also can generate resistance, a capacity that is readily enhanced with DC-targeted vaccines. During allergy, autoimmunity and transplant rejection, DCs instigate unwanted responses that cause disease, but, again, DCs can be harnessed to silence these conditions with novel therapies. Here we present some medical implications of DC biology that account for illness and provide opportunities for prevention and therapy.

Taking dendritic cells into medicine

Cancer immunotherapy attempts to harness the power and specificity of the immune system to treat tumours. The molecular identification of human cancer-specific antigens has allowed the development of antigen-specific immunotherapy. In one approach, autologous antigen-specific T cells are expanded ex vivo and then re-infused into patients. Another approach is through vaccination; that is, the provision of an antigen together with an adjuvant to elicit therapeutic T cells in vivo. Owing to their properties, dendritic cells (DCs) are often called 'nature's adjuvants' and thus have become the natural agents for antigen delivery. After four decades of research, it is now clear that DCs are at the centre of the immune system owing to their ability to control both immune tolerance and immunity. Thus, DCs are an essential target in efforts to generate therapeutic immunity against cancer.

Cancer immunotherapy via dendritic cells

Microbial infections are recognized by the innate immune system both to elicit immediate defense and to generate long-lasting adaptive immunity. To detect and respond to vastly different groups of pathogens, the innate immune system uses several recognition systems that rely on sensing common structural and functional features associated with different classes of microorganisms. These recognition systems determine microbial location, viability, replication and pathogenicity. Detection of these features by recognition pathways of the innate immune system is translated into different classes of effector responses though specialized populations of dendritic cells. Multiple mechanisms for the induction of immune responses are variations on a common design principle wherein the cells that sense infections produce one set of cytokines to induce lymphocytes to produce another set of cytokines, which in turn activate effector responses. Here we discuss these emerging principles of innate control of adaptive immunity.

Control of adaptive immunity by the innate immune system

Functional Specializations of Human Epidermal Langerhans Cells and CD14+ Dermal Dendritic Cells

Immunization to multiple defined tumor antigens for specific immune
therapy of human cancer has thus far proven difficult. Eighteen
HLA A*0201+
patients with metastatic melanoma received injections s.c. of
CD34+progenitor-derived autologous dendritic cells (DCs), which included
Langerhans cells. DCs were pulsed with peptides derived from four
melanoma antigens [(MelAgs) MelanA/MART-1, tyrosinase, MAGE-3, and
gp100], as well as influenza matrix peptide (Flu-MP) and keyhole
limpet hemocyanin (KLH) as control antigens. Overall immunological
effects were assessed by comparing response profiles using marginal
likelihood scores. DC injections were well tolerated except for
progressive vitiligo in two patients. DCs induced an immune response to
control antigens (KLH, Flu-MP) in 16 of 18 patients. An enhanced immune
response to one or more MelAgs was seen in these same 16 patients,
including 10 patients who responded to >2 MelAgs. The two patients
failing to respond to both control and tumor antigens experienced rapid
tumor progression. Of 17 patients with evaluable disease, 6 of 7
patients with immunity to two or less MelAgs had progressive disease 10
weeks after study entry, in contrast to tumor progression in only 1 of
10 patients with immunity to >2 MelAgs. Regression of >1 tumor
metastases were observed in seven of these patients. The overall
immunity to MelAgs after DC vaccination is associated with clinical
outcome (P = 0.015).

https://cancerres.aacrjournals.org/content/canres/61/17/6451.full.pdf

Immune and Clinical Responses in Patients with Metastatic Melanoma to CD34+ Progenitor-derived Dendritic Cell Vaccine

V-set and immunoglobulin domain-containing 4 (VSIG4) is a complement receptor of the immunoglobulin superfamily that is specifically expressed on tissue resident macrophages, and its many reported functions and binding partners suggest a complex role in immune function. VSIG4 is reported to have a role in immune surveillance as well as in modulating diverse disease phenotypes such as infections, autoimmune conditions, and cancer. However, the mechanism(s) governing VSIG4's complex, context-dependent role in immune regulation remain elusive. Here, we identify cell surface and soluble glycosaminoglycans (GAGs), specifically heparan sulfates, as novel binding partners of VSIG4. We demonstrate that genetic deletion of heparan sulfate synthesis enzymes or cleavage of cell-surface heparan sulfates reduced VSIG4 binding to the cell surface. Furthermore, binding studies demonstrate that VSIG4 interacts directly with heparan sulfates, with a preference for highly sulfated moieties and longer GAG chains. To assess the impact on VSIG4 biology, we show that heparan sulfates compete with known VSIG4 binding partners C3b and iC3b. Further, mutagenesis studies indicate this competition occurs through overlapping binding epitopes for heparan sulfates and complement on VSIG4. Together these data suggest a novel role for heparan sulfates in VSIG4-dependent immune modulation.

/pdf/vsig4-interaction-with-heparan-sulfates-inhibits-vsig4-ecw4a4ii.pdf

VSIG4 interaction with heparan sulfates inhibits VSIG4-complement binding.

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Functional Specializations of Human Epidermal Langerhans Cells and CD14+ Dermal Dendritic Cells

Immune and Clinical Responses in Patients with Metastatic Melanoma to CD34+ Progenitor-derived Dendritic Cell Vaccine

VSIG4 interaction with heparan sulfates inhibits VSIG4-complement binding.