Impact of dendritic cell activation/maturation on immune system to produce a response

Dendritic cells, or DCs, are vital for managing immune responses and self-antigen
sensitization. After DC were identified by Steinman and Cohn in lymphoid tissues as cells
with the rare capability to stimulate immature antigen-specific T lymphocytes, it was
immediately realised that DC could occur in at least two separate stages separated by
structural, functional, and phenotypic alterations. The definition of DC maturation resulted
from this realisation. There are various subsets of DC that display exceptional functional
specialisation and sensitivity in their positions in immunity and tolerance in both non-
lymphoid and lymphoid tissues of mammals.

Basic DC precursors that develop into plasmacytoid dendritic cells (pDCs) and intermediary
cells known as pre-conventional dendritic cells are the building blocks from which the
mononuclear phagocyte system's dendritic cells are made (pre-cDC). Before moving into
lymphoid and non-lymphoid tissues, wherein they segregate into cDC, pre-cDC transit from
the bone marrow and momentarily circulate in the bloodstream. When there is inflammation
in non-lymphoid tissues, pDC can also access bloodstream cells, but only in the event of
secondary lymphoid organs. Investigation of the secondary lymphoid organs (spleen, lymph
nodes) and non-lymphoid tissues has revealed numerous distinct populations of cDC (skin,
gut, lung, skeletal muscle, and liver). Irrespective of their structural site or species of origin,
cDC can be separated into two main subgroups based on their morphology, gene expression
patterns, physiological specialisation, and the regulatory sequences that define their growth.

Mouse and human DC fractions can be divided into four main subsets, regardless of whether
they are located in the parenchyma of non-lymphoid organs or secondary lymphoid tissues.
They are known as pDC, moDC, Xcr1+, and CD11b+.

The production of CD8 or CD103 on the exterior of the cell was initially used to categorise a
subgroup of cDC, commonly known as CD8-type cDC. However, intestinal cDC from a
distinct subgroup known as CD11b+ cDC also exhibit CD103, indicating that CD8
production is not a "universal" feature of this fraction. Contrarily, recent research has shown
that the chemokine receptor Xcr1 is very specific for CD8-type cDC. The C-type lectin
Clec9a specifically expresses pDC, a subgroup of DC progenitors, and CD8-type cDC (also
known as Dngr1). Xcr1+ cDC is another name for CD8-type cDC.

The other important subset of cDC is the CD11b+ cDC. The phenotypical resemblance
between CD11b+ cDC and other mononuclear phagocyte cells, particularly monocyte-
derived DC (moDC) and tissue-dweller macrophages, has perplexed researchers. All cDC
undergo continuous modification from bone marrow precursors in a way that relies on the
cytokine Flt3L but is separate from the CCR2 chemokine receptor. This includes CD11b+
cDC. They have brief half-lives (roughly 3-5 days in LT and marginally higher in NLT such
as the kidneys or lung). Flt3L is not required for th e development and maintenance of bone
marrow progenitor-derived moDC and tissue-resident macrophages, although CCR2
expression is.

These distinct developmental requirements allowed us to categorically distinguish CD11b+

cDC from moDC and macrophages as CD11b+ Ly6C+ CD64+ MerTK+ cells. It should be
noted that the high-affinity IgG receptor FcRI and CD64 are similar. MerTK, a receptor
protein-tyrosine kinase, recognises apoptotic cells and stimulates their absorption by
phagocytic cells while inhibiting their stimulation, especially through conflicting signaling by
the receptor protein for type I interferons (IFN-I). Human cDC that express CD1c (BDCA1)
and mouse CD11b+ cDC share a gene profile, suggesting that these cells are likely functional
homologs.

Functionally, mouse pDC are unique in their remarkable capability to create significant
quantities of IFN-I in relation to viral activation. They have a shape that resembles a steady-
state plasma cell, as suggested by their name. However, they build on dendrites after getting
triggered. A mouse pDC could be known as CD11b-CD11cint Bst2hi or CD11b-SiglecH+.
On activated pDCs, the synthesis of this marker is further increased, and some pDCs produce
it in a constant state. To avoid mistakenly include CD8+ pDC in the subgroup of Xcr1+ cDC,
which could happen if only CD11c and CD8 are employed to characterise the latter, caution
must be exercised.

Monocyte-originated inflammatory DC (Inf-moDC), which grow in inflamed and irritated

tissues and eventually disappear, are created upon inflammatory response from extravascular
Ly6Chi (classical) blood monocytes. Inf-moDC has been discovered in both human and sick
mice conditions. In particular inflammatory circumstances or in the course of infections by
viral, bacterial, parasitic, and fungal pathogens, MoDC can develop into tumour necrosis
factor (TNF) and inducible NO synthase (iNOS)-generating DC (Tip-DC) with significant
antimicrobial effector capabilities.

Maturation of DC: One of the most crucial aspects of DC biology is the development of DCs'
functional maturity. Some of the crucial characteristics that are gained during this complex
process include migration, T-cell co-stimulation, and antigen processing and presentation. As
mentioned in literature, maturation of DC is a multimodal procedure that may impart special
useful properties. In stable-state, non-lymphoid tissue (NLT)-cDC and lymphoid tissue (LT)-
cDC are categorised as immature or resting, a surface structure marked by a low surface
abundance of co-stimulatory proteins and MHC class II receptors (e.g., CD80, CD40 and
CD86). In response to an injury, infection, or vaccination activation, LT-cDC and NLT-cDC
undergo a maturation programme that equips them with the ability to promote the clonal
proliferation of naive T cells that are specific for an antigen and their subsequent
diversification into effector T cells.

In this situation, immunogenic development of cDC results in the increased expression of co-
stimulatory and MHC class II proteins at the cell membrane, the CCR7-reliant relocation to
T-cell-rich zones in lymph nodes, and the ability to produce cytokines encouraging the
differentiation of immature antigen-specific T cells into effector cells in addition to the
activation of several other types of immune cells. To enable the adjustment of T-cell
polarisation to the unique characteristics of the danger, cDC can create various cytokines and
cause the development of various kinds of effector T cells in response to the stimuli they
sense.

All DC subgroups, as well as other antigen-producing cells like macrophages, are furnished
with an array of pattern-recognition receptors (PRRs), which are able to recognise molecular
signatures of invasive pathogens or endogenous "threat" signals and trigger an immune
response. These highly diversified PRRs are expressed both inside and outside of the cell, and
they are capable of sensing a vast variety of molecules, which includes proteins, lipids,
carbohydrates, and nucleic acids. The Toll-like receptors family of PRRs on DC is the most
extensively researched (TLRs). In order to prime naive T cells in reaction to infection and
functionally mature DC into immunogenic DC, as well as to couple innate and adaptive
immunity, it is believed that TLRs on DC must be activated.

Importantly, some TLRs can recognise host compounds, such the TLRs that can detect
nucleic acids (TLR3, TLR7 and TLR9). These endogenous TLR agnostic proteins may
contribute to the autoimmune disorders, rheumatoid arthritis (RA), psoriasis and systemic
lupus erythematosus by inappropriately activating DC (SLE). It has been recently
demonstrated that TLR signalling in DC is essential for maintaining immunologic
homeostasis and sensitivity to gut microbiota. TLR-mediated identification of bacterial
products might also play a significant role in tissue homeostasis, with the intestine serving as
the most notable example. In the intestine, blocking TLR signalling results in impeded barrier
function and inflammation.