Dendritic cell subsets in T cell programming: location dictates function

Abstract

Dendritic cells (DCs) can be viewed as translators between innate and adaptive immunity. They integrate signals derived from tissue infection or damage and present processed antigen from these sites to naive T cells in secondary lymphoid organs while also providing multiple soluble and surface-bound signals that help to guide T cell differentiation. DC-mediated tailoring of the appropriate T cell programme ensures a proper cascade of immune responses that adequately targets the insult. Recent advances in our understanding of the different types of DC subsets along with the cellular organization and orchestration of DC and lymphocyte positioning in secondary lymphoid organs over time has led to a clearer understanding of how the nature of the T cell response is shaped. This Review discusses how geographical organization and ordered sequences of cellular interactions in lymph nodes and the spleen regulate immunity.

Fig. 1 ∣. Functionally specialized conventional and non-conventional dendritic cell subsets and related lineages.

The recent discovery of sets of particular transcription factors that define lineage ontogeny now allows for a clear distinction between monocytes and dendritic cells (DCs) as well as between different subsets of conventional DCs (cDCs) and non-cDCs^,. cDCs derive from a common DC precursor (CDP), require the transcription factor FMS-like tyrosine kinase 3 ligand (FLT3L) for development and express, but do not require, the transcription factor ZBTB46 (REFS^,). The genetic signature of cDCs from different tissues is similar but differs from that of plasmacytoid DCs (pDCs), monocytes and macrophages. As professional antigen-presenting cells, their primary function is to prime naive T cells. The BATF3-dependent and IRF8-dependent type 1 cDC (cDC1) subset expresses the chemokine XC receptor 1 (XCR1)^,, (in both mice and humans) and includes DCs that may express different surface markers such as CD8αα, DEC-205 or CD103. Shared expression of the surface receptor Langerin by both Langerhans cells (LCs) and dermal cDC1s initially caused confusion about the relative role of LCs in T cell priming, but newer models delineate the specific function of each population. The IRF4-dependent cDC2 subset can be identified by expression of surface markers CD11b, DC immunoreceptor 2 (DCIR2) (by staining with the antibody 33D1), CD301b (MGL2), CD4 or signal regulatory protein-α (SIRPα), depending on the tissue investigated^,,,,. This subset includes the CD4⁺CD11b⁺ESAM⁺ DCs, which are dependent on the expression of NOTCH2 and the DNA-binding protein RBPJ, but also the double-negative (CD4⁻CD8⁻) DCs in the spleen, which are ESAM^low but CD11b⁺ (REFS^,). Recent studies from other mouse tissues as well as human blood and lymph nodes (LNs) have similarly found two subsets of cDC2s^,- (this division has not been depicted). Although some pDCs share a common developmental precursor with cDCs, they require distinct differentiation factors, express a unique pattern of surface markers and are functionally distinct from cDCs^,. This includes being poor antigen-presenting cells for naive T cells (except under rare circumstances or potentially a unique subset) but robust producers of type I interferons^,. One of the original DCs, LCs, has been re-classified with macrophages on the basis of ontogeny but performs many functions overlapping with cDCs. Both tissue macrophages and LCs derive from embryonic precursors and self-renew in situ (circular arrow indicates self-renewal in tissues). However, under inflammatory conditions, bone marrow-derived monocytes can differentiate to help repopulate both of these cells types. Tissue-resident macrophages maintain tissue homeostasis and a variety of other functions (reviewed previously). Macrophage populations also exist in LNs, but their roles are distinct from DCs; they are poor activators of naive T cells, even when presenting cognate antigen^,,, but are potent at clearing apoptotic cells and promoting B cell activation^,. Monocyte-derived DCs (MoDCs) include cells with a variety of functions, including TNF/iNOS-producing (TIP)-DCs as well as a difficult-to-define, heterogeneous group of cells collectively termed inflammatory DCs (iDCs). Like classical monocytes, MoDCs are dependent on the cytokine macrophage colony-stimulating factor (M-CSF), do not express the transcription factor ZBTB46 and depend on the chemokine receptor CC-chemokine receptor 2 (CCR2) for recruitment into inflammatory sites. They typically perform functions in the tissues such as antigen presentation to effector T cells, pathogen clearance and cytokine production. iDCs are induced during states of inflammation and have a mixed ontogeny and function that remain to be fully characterized^,,. Some iDCs have, however, been shown to migrate to LNs and act more like cDCs, but these iDCs may in fact arrive in LNs through the blood via a CCR7-independent mechanism^,. Select markers for each population are shown, with those in parentheses indicating heterogeneous or tissue-restricted expression. All populations express CD11c except monocytes. Below each population, the dominant (but not sole) function of each population is indicated. BDCA, blood DC antigen; CLEC9A, C-type lectin domain-containing 9A ; CLP, common lymphoid progenitor ; CX₃CR1, CX₃C-chemokine receptor 1; EPCAM, epithelial cell adhesion molecule; HSC, haematopoietic stem cell; MDP, macrophage DC progenitor ; SIGLECH, sialic acid-binding Ig-like lectin H. *Human-specific marker.

Fig. 2 ∣. Immunologic microanatomy of an LN.

Shown is a lymph node (LN) with entry sites of naive, effector and memory T cells and migratory dendritic cells (DCs). a ∣ The basic cellular structure of the LN divides it into T cell zones (TCZs) and B cell zones (BCZs). BCZs are also called follicles and may contain germinal centres depending on activation state. The basic anatomical structure of the LN divides it into the cortex (nearest the capsule and afferent lymphatics), paracortex (in between) and medulla (nearest the exiting efferent lymphatics). The area between the TCZ and BCZ, which contains fibroblastic reticular cell networks and many high endothelial venules (HEVs), has been called the cortical ridge. The cortex is commonly thought of as the BCZ, whereas the paracortex is considered the TCZ; however, this over-simplifies the more intricate structure of the immune cellular compartments. The area between the B cell follicles through which immigrating cells from the lymph pass is called the interfollicular zone (IFZ) and can be considered part of the larger T cell–B cell border. No unique anatomical structure or cell is typically used to identify the IFZ, making a clear demarcation of this region difficult in some LNs. A cellular continuum exists between the outer paracortex and the IFZ and B cell regions, thereby forming a large and readily identifiable T cell–B cell border. The border can be distinguished from the follicles and deep TCZ by the overlap in T and B cell staining. Only spare and scattered T cells can be identified in the follicles, and few B cells can be identified in the TCZ. b ∣ Regions of effector T cell differentiation in an uninfected LN after immunization are depicted. The regions where CD4⁺ T helper 1 (T_H1), T_H2 and T_H17 cells and CD8⁺ cytotoxic T lymphocytes (CTLs) accumulate are shown. Depending on the nature of the immunogen, T_H1 cell induction has also been observed in the IFZ. c ∣ The geographical organization of migratory and LN-resident conventional DC (cDC) subsets, including type 1 cDCs (cDC1s) and type 2 cDCs (cDC2s), in LNs after immunization is depicted. At high doses of antigen (LN infection, footpad or auricular injection or high concentration of soluble antigen), all DC subsets have access to antigen. By contrast, at low antigen dose (subcutaneous or mucosal immunization or infection), primarily migratory DCs would deliver antigen to LNs; this antigen might then be shared with LN-resident DCs. MSM, medullary sinus macrophage; SCS, subcapsular sinus; T_FH cell, T follicular helper cell. *The sub-anatomic LN region for T_H17 cell differentiation is based on indirect evidence.

Fig. 3 ∣. Immunologic microanatomy of the spleen.

The spleen is divided by function and structure into red pulp (RP) and white pulp (WP); between these two regions is the marginal zone (MZ) (in mice), which is functionally equivalent to the less-well-characterized perifollicular zone in humans (not shown)^,. These regions correspond to the subcapsular sinus of the lymph node (LN); in both LN and spleen, these are the regions of antigen delivery from the periphery and antigen sampling by innate immune cells such as macrophages. The RP contains multiple innate cell populations that help clear aged red cells and debris from the circulation as well as fight systemic infections but also houses particular effector lymphocyte populations. The MZ contains a conduit between the RP and WP called the bridging channel, which is thought to be a site of activated lymphocyte exit from the WP and an area where (in mice) MZ B cells produce T cell-independent antibodies^,,. The bridging channel lacks CD169⁺ marginal zone metallophilic macrophages, which helps to define the border between the WP and RP and is the site where type 2 conventional dendritic cells (cDC2s) reside at steady state. Most naive lymphocytes are located in the WP and reside in distinct zones analogous to those found in LNs. Similar to the fibroblastic reticular cell and follicular dendritic cell structural framework in the LN, stromal cells establish the cellular organization of the WP^,. B cells reside in WP follicles just beneath the MZ, surrounding a central T cell zone (TCZ) (also called the periarteriolar lymphoid sheath (PALS)). Similar to LNs, the WP is where adaptive immune responses are generated to blood-borne antigens. Part a shows the general spleen structure. Part b shows the geographical organization of dendritic cell (DC) and T cell subsets at steady state. cDC1 and cDC2 subsets are depicted in green and blue, respectively. WP-resident and migratory cDC2s are proposed but cannot currently be distinguished (whether the markers CD4 and ESAM are differentially expressed on the basis of location remains to be determined). Part c shows the geographical organization of DC and T cell subsets during inflammation. BCZ, B cell zone; XCR1; chemokine XC receptor 1.