Skin immune system

Author:  Dr Yuliya Velykoredko MD, Dermatology Resident, and Dr Michal Bohdanowicz MD PhD, Dermatology ResidentUniversity of Toronto, Canada.  DermNet New Zealand Editor in Chief: Hon A/Prof Amanda Oakley, Dermatologist, Hamilton, New Zealand. July 2017.


Our skin plays a vital role in protection from the external environment. Its roles include:

Peripheral lymphoid organs include spleen, lymph nodes and skin (also called skin-associated lymphoid tissue or SALT).

* Reprinted by permission from Macmillan Publishers Ltd: Nestle, F. O., Di Meglio, P., Qin, J., & Nickoloff, B. J. (2009). Skin immune sentinels in health and disease. Nature Reviews.Immunology, 9(10), 679-91.

Overview of the skin immune system

The skin immune systems are innate (non-specific) and adaptive (specific). Immune cells inhabit the epidermis and dermis

The key immune cells in the epidermis are:

The dermis has blood and lymph vessels and numerous immune cells, including:

There is continuous trafficking of immune cells between the skin, draining lymph nodes and blood circulation. The skin microbiome also contributes to the homeostasis of the skin immune system.

Innate immune response

The innate immune response is quick and is not dependent on previous immunological memory.


Keratinocytes are the predominant cells in the epidermis. They act as the first line of innate immune defence against infection. They express toll-like receptors (TLRs), which are pattern-recognition receptors (PRRs) that detect conserved molecules on pathogens and trigger an inflammatory response.

Keratinocytes communicate with the rest of the immune system through:

Macrophages and neutrophils

Macrophages are phagocytic cells that can discriminate between self and foreign molecules. After phagocytosis by macrophages, an invading pathogen is killed inside the cell. Activated macrophages recruit neutrophils to enter the circulation and travel to sites of infection or inflammation.

Neutrophils are the “first responders”. They directly attack micro-organisms by phagocytosis and by degranulation of toxic substances.

Dendritic cells

Epidermal and dermal dendritic cells are involved in both the innate and adaptive immune responses. In the innate response:

Natural killer cells

NK cells are cytotoxic lymphocytes that can eliminate virally infected cells and cancer cells without antigen presentation or priming.

Mast cells

Mast cells store pre-formed inflammatory mediators such as histamine within cytoplasmic granules. Mast cells possess a high-affinity surface receptor FcεRI that binds specific triggering signals. The cells degranulate upon contact with stimuli such as allergens, venoms, IgE antibodies, and medications.

The mediators can result in pruritic weals due to increased vascular permeability (urticaria). Mast cell activation can rarely lead to anaphylaxis, characterised by bronchoconstriction, dizziness and syncope.


Eosinophils enter the skin in pathologic conditions such as parasitic infestations and atopic dermatitis.

Complement system

The complement system is an enzymatic cascade of over 20 different proteins normally found in the blood. When an infection is present, the system is sequentially activated leading to events that help destroy the invading organism.

The complement system can also attract neutrophils to the site of infection.

Adaptive immune response

Compared to the innate immunity, the adaptive immune response is specific to a pathogen and takes a longer time to elicit. Adaptive immunity requires the production of specific T lymphocytes to identify an antigen with precision and B cells to produce specific antibodies that bind to the microbe in a “lock-and-key” fashion.

Antigen presentation

Dendritic cells (Langerhan cells and macrophages), or antigen presenting cells (APCs), identify antigens and present them to immature T cells. Epidermal Langerhan cells use their dendrites (arm-like projections) to survey the environment, especially the stratum corneum. The Langerhan cells bind pathogens to their TLRs, travel to draining lymph nodes, and present antigens to naïve lymphocytes. Antigen presentation requires internalisation of pathogen, processing inside the cell, and display of a short peptide on the surface of APC on a major histocompatibility complex (MHC) molecule.

There are two major types of MHC: MHC-I and MHC-II.

T cells

The skin contains resident T cells and recruited circulating T cells. Effective antigen presentation allows for naïve T cells to differentiate into effector T cells:

T cells are unable to recognise pathogens directly. The receptor on the surface of a T cell binds to the peptide/MHC complex on the surface of the APC.  

Th cells include Th1, Th2, Th17 and Th22 subtypes. Each subtype is associated with specific signalling cytokines and effector functions.

Th1 cells produce a cell-mediated immune response to kill intracellular pathogens.

Th2 cell activation leads to B cell stimulation and antibody production.

Th17 cells produce IL-17 and IL-22 and play a role in protection from bacterial and fungal infections. Th22 cells produce IL-22 and TNF-a. Both Th17 and Th22 cells play a role in the pathogenesis of psoriasis.

B cells

B lymphocytes are unique in having the ability to produce antibodies (immunoglobulins) that can bind to specific antigens. Antibody effector functions are:

To produce antibodies, B cells require cytokine signalling and stimulatory signals from Th cells. This takes place in secondary lymphoid organs such as lymph nodes.

Upon re-exposure to the same antigen and follicular dendritic cells, B cells are activated to produce specific antibodies.

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