View source for Cell-mediated immunity

{{short description|Immune response that does not involve antibodies}}

[[File:Killer T cells surround a cancer cell.png|thumb|upright=1.25|Immunofluorescence micrograph of three [[cytotoxic T cell]]s (outer three) surrounding a cancer cell. Lytic granules (red) are secreted at the contact site, killing the target. Cytotoxic T cells are powerful agents of cellular immunity.]]

'''Cellular immunity''', also known as '''cell-mediated immunity''', is an [[immune response]] that does not rely on the production of [[Antibody|antibodies]]. Rather, cell-mediated immunity is the activation of [[phagocyte]]s, antigen-specific [[Cytotoxic T cell|cytotoxic T-lymphocytes]], and the release of various [[cytokines]] in response to an [[antigen]].

==History==

In the late 19th century [[Hippocrates#Hippocratic theory|Hippocratic tradition]] medicine system, the immune system was imagined into two branches: [[humoral immunity]], for which the protective function of immunization could be found in the humor (cell-free [[bodily fluid]] or [[blood plasma|serum]]) and '''cellular immunity''', for which the protective function of immunization was associated with cells. [[CD4]] cells or [[T helper cell|helper T cell]]s provide protection against different [[pathogens]]. [[Naive T cells]], which are immature T cells that have yet to encounter an [[antigen]], are converted into activated effector [[T cell]]s after encountering [[antigen-presenting cells]] (APCs). These APCs, such as [[macrophages]], [[dendritic cells]], and [[B cells]] in some circumstances, load antigenic peptides onto the [[major histocompatibility complex]] (MHC) of the cell, in turn presenting the [[peptide]] to receptors on T cells. The most important of these APCs are highly specialized dendritic cells; conceivably operating solely to ingest and present antigens.<ref name="auto">{{Cite journal |last1=Ross Russell |first1=Amy L |last2=Dryden |first2=Matthew S |last3=Pinto |first3=Ashwin A |last4=Lovett |first4=Joanna K |date=2018-10-03 |title=Lyme disease: diagnosis and management |url=http://dx.doi.org/10.1136/practneurol-2018-001998 |journal=Practical Neurology |volume=18 |issue=6 |pages=455–464 |doi=10.1136/practneurol-2018-001998 |pmid=30282764 |s2cid=52915054 |issn=1474-7758|url-access=subscription }}</ref> Activated effector T cells can be placed into three functioning classes, detecting [[peptide]] antigens originating from various types of [[pathogen]]: The first class being 1) [[Cytotoxic T cells]], which kill infected target cells by [[apoptosis]] without using cytokines, 2) [[T helper cell#Th1/Th2 model|T<sub>h</sub>1 cells]], which primarily function to activate macrophages, and 3) [[T helper cell#Th1/Th2 model|T<sub>h</sub>2 cells]], which primarily function to stimulate [[B cells]] into producing [[antibodies]].<ref name="auto"/>

In another ideology, the [[innate immune system]] and the [[adaptive immune system]] each comprise both [[humoral immunity|humoral]] and cell-mediated components. Some cell-mediated components of the innate immune system include myeloid [[phagocyte]]s, innate lymphoid cells ([[NK cell]]s) and [[intraepithelial lymphocyte]]s.<ref>{{Cite journal|last1= Romo |first1=MR |last2=Pérez-Martínez |first2=D |last3=Ferrer |first3=CC |year=2016 |title= Innate immunity in vertebrates: an overview|journal=Immunology |volume= 148|issue=2 |pages=125–139|doi= 10.1111/imm.12597|pmid=26878338 |pmc=4863567 |s2cid=35251844 |language=en}}</ref>

==Synopsis==
Cellular immunity protects the body through:
* T-cell mediated immunity or T-cell immunity: activating antigen-specific [[cytotoxic T cell]]s that are able to induce [[apoptosis]] in body cells displaying [[epitopes]] of foreign antigen on their surface, such as [[virus]]-infected cells, cells with [[intracellular bacteria]], and [[cancer]] cells displaying [[tumor]] antigens;
* [[Macrophage]] and [[natural killer cell]] action: enabling the destruction of pathogens via recognition and [[secretion]] of cytotoxic granules (for natural killer cells)<ref name="Eissmann">{{cite web |last1=Eissmann |first1=Philipp |title=Natural Killer Cells |url=https://www.immunology.org/public-information/bitesized-immunology/cells/natural-killer-cells |website=British Society for Immunology |access-date=8 November 2018}}</ref> and phagocytosis (for macrophages);<ref name="Saldana">{{cite web |last1=Saldana |first1=José |title=Macrophages |url=https://www.immunology.org/public-information/bitesized-immunology/cells/macrophages |website=British Society for Immunology |access-date=8 November 2018}}</ref> and
* Stimulating cells to secrete a variety of [[cytokine]]s that influence the function of other cells involved in adaptive immune responses and innate immune responses.<ref name="Eissmann" /><ref name="Saldana" />

Cell-mediated immunity is directed primarily at [[microbes]] that survive in [[phagocytes]] and microbes that infect non-phagocytic cells. It is most effective in removing [[Introduction to viruses|virus-infected cells]], but also participates in defending against [[fungi]], [[protozoan]]s, [[cancer]]s, and intracellular bacteria. It also plays a major role in [[transplant rejection]].

Type 1 immunity is directed primarily at [[viruses]], [[bacteria]], and [[protozoa]] and is responsible for activating [[macrophages]], turning them into potent effector cells. This is achieved by the secretion of [[interferon gamma]] and [[TNF]].{{citation needed|date=July 2023}}

==Overview==

CD4<sup>+</sup> [[T-helper cell]]s may be differentiated into two main categories:<ref name="The 3 major types of innate and adaptive cell-mediated effector immunity.">{{cite journal |last1=Annunziato |first1=F |last2=Romagnani |first2=C |last3=Romagnani |first3=S |title=The 3 major types of innate and adaptive cell-mediated effector immunity. |journal=The Journal of Allergy and Clinical Immunology |date=March 2015 |volume=135 |issue=3 |pages=626–35 |doi=10.1016/j.jaci.2014.11.001 |pmid=25528359|doi-access=free }}</ref>
# T<sub>H</sub>1 cells which produce [[interferon gamma]] and [[lymphotoxin alpha]],
# T<sub>H</sub>2 cells which produce [[Interleukin 4|IL-4]], [[Interleukin 5|IL-5]], and [[Interleukin 13|IL-13]].

A third category called [[T helper 17 cell]]s (T<sub>H</sub>17) were also discovered which are named after their secretion of [[Interleukin 17]].

CD8<sup>+</sup> [[cytotoxic T-cell]]s may also be categorized as:<ref name="The 3 major types of innate and adaptive cell-mediated effector immunity." />
# T<sub>c</sub>1 cells,
# T<sub>c</sub>2 cells.

Similarly to CD4<sup>+</sup> T<sub>H</sub> cells, a third category called T<sub>C</sub>17 were discovered that also secrete IL-17.

As for the [[Innate lymphoid cell|ILCs]], they<sup>''[Clarification needed.]''</sup> may be classified into three main categories<ref name="The 3 major types of innate and adaptive cell-mediated effector immunity." />
# [[ILC1]] which secrete type 1 cytokines,
# [[ILC2]] which secrete type 2 cytokines,
# [[ILC3]] which secrete type 17 cytokines.

==Development of cells==
All type 1 cells begin their development from the [[common lymphoid progenitor]] (CLp) which then differentiates to become the common innate lymphoid progenitor (CILp) and the t-cell progenitor (Tp) through the process of [[lymphopoiesis]].<ref name="The 3 major types of innate and adaptive cell-mediated effector immunity." /><ref name="Innate lymphocytes-lineage, localization and timing of differentiation">{{cite journal |last1=Kansler |first1=Emily R. |last2=Li |first2=Ming O. |title=Innate lymphocytes—lineage, localization and timing of differentiation |journal=Cellular & Molecular Immunology |date=July 2019 |volume=16 |issue=7 |pages=627–633 |doi=10.1038/s41423-019-0211-7|pmid=30804475 |pmc=6804950 |doi-access=free }}</ref>

Common innate lymphoid progenitors may then be differentiated into a natural killer progenitor (NKp) or a common helper like innate lymphoid progenitor (CHILp). NKp cells may then be induced to differentiate into [[natural killer cell]]s by [[Interleukin 15|IL-15]]. CHILp cells may be induced to differentiate into [[ILC1]] cells by [[Interleukin 15|IL-15]], into [[ILC2]] cells by [[Interleukin 7|IL-7]] or [[ILC3]] cells by [[Interleukin 7|IL-7]] as well.<ref name="The 3 major types of innate and adaptive cell-mediated effector immunity." /><ref name="Innate lymphocytes-lineage, localization and timing of differentiation" />

T-cell progenitors may differentiate into naïve CD8<sup>+</sup> cells or naïve CD4<sup>+</sup> cells. Naïve CD8<sup>+</sup> cells may then further differentiate into T<sub>C</sub>1 cells upon [[Interleukin 12|IL-12]] exposure, [IL-4] can induce the differentiation into T<sub>C</sub>2 cells and [[Interleukin 1|IL-1]] or [[Interleukin 23|IL-23]] can induce the differentiation into T<sub>C</sub>17 cells. Naïve CD4<sup>+</sup> cells may differentiate into T<sub>H</sub>1 cells upon [[Interleukin 12|IL-12]] exposure, T<sub>H</sub>2 upon [[Interleukin 4|IL-4]] exposure or T<sub>H</sub>17 upon [[Interleukin 1|IL-1]] or [[Interleukin 23|IL-23]] exposure.<ref name="The 3 major types of innate and adaptive cell-mediated effector immunity." /><ref name="Innate lymphocytes-lineage, localization and timing of differentiation" />

==Type 1 immunity==
Type 1 immunity makes use of the type 1 subset for each of these cell types. By secreting [[interferon gamma]] and [[TNF]], T<sub>H</sub>1, T<sub>C</sub>1, and group 1 ILCS activate macrophages, converting them to potent effector cells.  It provides defense against intracellular [[bacteria]], [[protozoa]], and [[viruses]]. It is also responsible for [[inflammation]] and [[autoimmunity]] with diseases such as [[rheumatoid arthritis]], [[multiple sclerosis]], and [[inflammatory bowel disease]] all being implicated in type 1 immunity. Type 1 immunity consists of these cells:<ref name="The 3 major types of innate and adaptive cell-mediated effector immunity." />
* CD4+ T<sub>H</sub>1 cells
* CD8<sup>+</sup> cytotoxic T cells (T<sub>c</sub>1)
* T-Bet<sup>+</sup> [[interferon gamma]] producing group 1 ILCs(ILC1 and Natural killer cells)

'''CD4<sup>+</sup> T<sub>H</sub>1 Cells'''

It has been found in both [[mice]] and [[humans]] that the signature cytokines for these cells are [[interferon gamma]] and [[lymphotoxin alpha]]. The main cytokine for differentiation into T<sub>H</sub>1 cells is IL-12 which is produced by [[dendritic cell]]s in response to the activation of [[pattern recognition receptor]]s. [[T-bet]] is a distinctive [[transcription factor]] of T<sub>H</sub>1 cells. T<sub>H</sub>1 cells are also characterized by the expression of chemokine receptors which allow their movement to sites of inflammation. The main [[chemokine receptors]] on these cells are [[CXCR3A]] and [[CCR5]]. [[Epithelial cells]] and [[keratinocytes]] are able to recruit T<sub>H</sub>1 cells to sites of infection by releasing the chemokines [[CXCL9]], [[CXCL10]] and [[CXCL11]] in response to [[interferon gamma]]. Additionally, [[interferon gamma]] secreted by these cells seems to be important in downregulating [[tight junctions]] in the epithelial barrier.<ref name="The 3 major types of innate and adaptive cell-mediated effector immunity." />

'''CD8<sup>+</sup> T<sub>C</sub>1 Cells'''

These cells generally produce [[interferon gamma]]. Interferon gamma and [[Interleukin 12|IL-12]] promote differentiation toward T<sub>C</sub>1 cells. [[T-bet]] activation is required for both interferon gamma and cytolytic potential. [[CCR5]] and [[CXCR3]] are the main chemokine receptors for this cell.<ref name="The 3 major types of innate and adaptive cell-mediated effector immunity." />

'''Group 1 ILCs'''

Groups 1 ILCs are defined to include [[Innate lymphoid cell|ILCs]] expressing the transcription factor [[T-bet]] and were originally thought to only include [[natural killer cell]]s. Recently, there have been a large amount of NKp46<sup>+</sup> cells that express certain master [transcription factor]s that allow them to be designated as a distinct lineage of natural killer cells termed ILC1s. ILC1s are characterized by the ability to produce [[interferon gamma]], [[TNF]], [[GM-CSF]] and [[Interleukin 2|IL-2]] in response to cytokine stimulation but have low or no cytotoxic ability.<ref name="The 3 major types of innate and adaptive cell-mediated effector immunity." />

==See also==
* [[Immune system]]
* [[Humoral immunity]] (vs. cell-mediated immunity)
* [[Immunity (medical)|Immunity]]

==References==
{{reflist}}

===Bibliography===
* [https://www.britannica.com/science/cell-mediated-immunity Cell-mediated immunity] (Encyclopædia Britannica)
* [https://www.ncbi.nlm.nih.gov/books/NBK10762/ Chapter 8:T Cell-Mediated Immunity ] Immunobiology: The Immune System in Health and Disease. 5th edition.
* [https://pubmed.ncbi.nlm.nih.gov/25528359/] The 3 major types of innate and adaptive cell-mediated effector immunity
* [https://pubmed.ncbi.nlm.nih.gov/30804475/#:~:text=Innate%20lymphocytes-lineage,%20localization%20and%20timing%20of%20differentiation%20Innate, functions%20in%20steady-state%20homeostasis%20and%20during%20immune%20challenge.] Innate lymphocytes-lineage, localization and timing of differentiation

==Further reading==
* [https://web.archive.org/web/20130507192352/http://missinglink.ucsf.edu/lm/immunology_module/prologue/objectives/obj07.html Cell-mediated immunity: How T cells recognize and respond to foreign antigens]

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[[Category:Immunology]]
[[Category:T cells|Helper]]
[[Category:Human cells]]
[[Category:Macrophages| ]]
[[Category:Phagocytes]]
[[Category:Cell biology]]
[[Category:Immune system]]
[[Category:Lymphatic system]]
[[Category:Infectious diseases]]
[[Category:Apoptosis| ]]
[[Category:Cell signaling]]
[[Category:Cytokines| ]]