Dendritic cells (DCs) are antigen-presenting cells with a unique ability to induce primary immune responses. DCs capture and transfer information from the outside world to the cells of the adaptive immune system. DCs are not only critical for the induction of primary immune responses, but may also be important for the induction of immunological tolerance, as well as for the regulation of the type of T cell-mediated immune response. Although our understanding of DC biology is still in its infancy, we are now beginning to use DC-based immunotherapy protocols to elicit immunity against cancer and infectious diseases.

Immunobiology of Dendritic Cells

Naive T lymphocytes travel to T-cell areas of secondary lymphoid organs in search of antigen presented by dendritic cells. Once activated, they proliferate vigorously, generating effector cells that can migrate to B-cell areas or to inflamed tissues. A fraction of primed T lymphocytes persists as circulating memory cells that can confer protection and give, upon secondary challenge, a qualitatively different and quantitatively enhanced response. The nature of the cells that mediate the different facets of immunological memory remains unresolved. Here we show that expression of CCR7, a chemokine receptor that controls homing to secondary lymphoid organs, divides human memory T cells into two functionally distinct subsets. CCR7- memory cells express receptors for migration to inflamed tissues and display immediate effector function. In contrast, CCR7+ memory cells express lymph-node homing receptors and lack immediate effector function, but efficiently stimulate dendritic cells and differentiate into CCR7- effector cells upon secondary stimulation. The CCR7+ and CCR7- T cells, which we have named central memory (TCM) and effector memory (TEM), differentiate in a step-wise fashion from naive T cells, persist for years after immunization and allow a division of labour in the memory response.

Two subsets of memory T lymphocytes with distinct homing potentials and effector functions

Breast cancer is characterized by a distinct metastatic pattern involving the regional lymph nodes, bone marrow, lung and liver. Tumour cell migration and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. Here we report that the chemokine receptors CXCR4 and CCR7 are highly expressed in human breast cancer cells, malignant breast tumours and metastases. Their respective ligands CXCL12/SDF-1α and CCL21/6Ckine exhibit peak levels of expression in organs representing the first destinations of breast cancer metastasis. In breast cancer cells, signalling through CXCR4 or CCR7 mediates actin polymerization and pseudopodia formation, and subsequently induces chemotactic and invasive responses. In vivo, neutralizing the interactions of CXCL12/CXCR4 significantly impairs metastasis of breast cancer cells to regional lymph nodes and lung. Malignant melanoma, which has a similar metastatic pattern as breast cancer but also a high incidence of skin metastases, shows high expression levels of CCR10 in addition to CXCR4 and CCR7. Our findings indicate that chemokines and their receptors have a critical role in determining the metastatic destination of tumour cells.

/pdf/involvement-of-chemokine-receptors-in-breast-cancer-1zppt60ctu.pdf

Involvement of chemokine receptors in breast cancer metastasis.

Heterogeneity of the macrophage lineage has long been recognized and, in part, is a result of the specialization of tissue macrophages in particular microenvironments. Circulating monocytes give rise to mature macrophages and are also heterogeneous themselves, although the physiological relevance of this is not completely understood. However, as we discuss here, recent studies have shown that monocyte heterogeneity is conserved in humans and mice, allowing dissection of its functional relevance: the different monocyte subsets seem to reflect developmental stages with distinct physiological roles, such as recruitment to inflammatory lesions or entry to normal tissues. These advances in our understanding have implications for the development of therapeutic strategies that are targeted to modify particular subpopulations of monocytes.

https://courses.washington.edu/conj514/readings/heinecke_reading4.pdf

Monocyte and macrophage heterogeneity

Regulatory T (T(reg)) cells mediate homeostatic peripheral tolerance by suppressing autoreactive T cells. Failure of host antitumor immunity may be caused by exaggerated suppression of tumor-associated antigen-reactive lymphocytes mediated by T(reg) cells; however, definitive evidence that T(reg) cells have an immunopathological role in human cancer is lacking. Here we show, in detailed studies of CD4(+)CD25(+)FOXP3(+) T(reg) cells in 104 individuals affected with ovarian carcinoma, that human tumor T(reg) cells suppress tumor-specific T cell immunity and contribute to growth of human tumors in vivo. We also show that tumor T(reg) cells are associated with a high death hazard and reduced survival. Human T(reg) cells preferentially move to and accumulate in tumors and ascites, but rarely enter draining lymph nodes in later cancer stages. Tumor cells and microenvironmental macrophages produce the chemokine CCL22, which mediates trafficking of T(reg) cells to the tumor. This specific recruitment of T(reg) cells represents a mechanism by which tumors may foster immune privilege. Thus, blocking T(reg) cell migration or function may help to defeat human cancer.

Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival.

Thymus settling by precursor cells is essential for the production of T cells, yet the immigration requirements are poorly defined. P-selectin and CC chemokine receptor-9 (CCR9) are involved, and settling is favored when existing residents have moved on. A new study strengthens the correlation between niche emptying and the induction of thymic P-selectin and CCR9 ligand, and provides evidence for feedback from the periphery to thymic P-selectin expression via sphingosine-1-phosphate.

/pdf/settling-the-thymus-immigration-requirements-3l3jl5imuo.pdf

Settling the thymus: immigration requirements

Immune system function depends on getting the right cells to the right place at the right time. Inadequate or inappropriate migration of immune cells is involved in many and perhaps all types of immunological disease. Chemokines have been identified as critical guidance factors that help recruit and position cells at each stage of the immune response. Two-photon imaging of intact lymphoid organs has provided evidence of chemotactic migration of lymphocytes in lymphoid organs. Our work on the role of chemokines as organizers of lymphoid tissues will be briefly summarized. Lymphocyte egress from lymphoid organs is necessary for immune surveillance and for effector cell trafficking to sites of inflammation. Sphingosine-1-phosphate (SIP) receptor 1 and the circulatory lipid, S1P, are required for lymphocyte egress from lymphoid organs. We have recently identified CD69 as a regulator of SIP1 and controller of lymphocyte egress. Current molecular understanding of the lymphocyte egress process will be discussed.

Specifying the patterns of immune cell migration.

Th1 Cell Induction in Lymph Nodes According to a Red-Blue Chemokine Map

Lymph nodes (LNs), Peyer’s patches (PPs), and the spleen are command centers for the adaptive immune system, bringing together Ags and immune cells for the initiation of antipathogen offensives. The anatomy of these organs has been studied for over 100 years, and their organization into thymus-

Blown Away: The Unexpected Role of Lymphotoxin in Lymphoid Organ Development

The marginal zone (MZ) of the spleen contains multiple cell types that are involved in mounting rapid immune responses against blood-borne pathogens, including conventional dendritic cells (cDCs) and MZ B cells. MZ B cells develop later than other B cell types and are sparse in neonatal mice. Here, we show that cDC2s are abundant in the MZ of neonatal compared with adult mice. We find that conditions associated with reduced MZ B cell numbers in adult mice cause increased cDC2 occupancy of the MZ. Treatment with the S1PR1-modulating drug, FTY720, causes cDC2 movement into the MZ through the indirect mechanism of displacing MZ B cells into follicles. Splenic cDC2s express high amounts of α4β1 and αLβ2 integrins and depend on these integrins and the adaptor Talin for their retention in blood-exposed regions of the spleen. Splenic CD4 T cell activation by particulate antigens is increased in mice with higher cDC2 density in the MZ, including in neonatal mice. Our work establishes requirements for homeostatic cDC2 positioning in the spleen and provides evidence that localization in blood-exposed regions around the white pulp augments cDC2 capture of particulate antigens. We suggest that MZ positioning of cDC2s partially compensates for the lack of MZ B cells during the neonatal period.

/pdf/requirements-for-cdc2-positioning-in-blood-exposed-regions-1a8bonq2nc.pdf

Jason G. Cyster

Papers

Settling the thymus: immigration requirements

Specifying the patterns of immune cell migration.

Th1 Cell Induction in Lymph Nodes According to a Red-Blue Chemokine Map

Blown Away: The Unexpected Role of Lymphotoxin in Lymphoid Organ Development

Requirements for cDC2 positioning in blood-exposed regions of the neonatal and adult spleen