# Cell-mediated immunity

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

## History

In the late 19th century 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 serum) and cellular immunity, for which the protective function of immunization was associated with cells. CD4 cells or helper T cells 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 cells 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. 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$_h$1 cells, which primarily function to activate macrophages, and 3) T$_h$2 cells, which primarily function to stimulate B cells into producing antibodies.
In another ideology, the innate immune system and the adaptive immune system each comprise both humoral and cell-mediated components. Some cell-mediated components of the innate immune system include myeloid phagocytes, innate lymphoid cells (NK cells) and intraepithelial lymphocytes.

## Synopsis

Cellular immunity protects the body through:
* T-cell mediated immunity or T-cell immunity: activating antigen-specific cytotoxic T cells 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) and phagocytosis (for macrophages); and
* Stimulating cells to secrete a variety of cytokines that influence the function of other cells involved in adaptive immune responses and innate immune responses.
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 virus-infected cells, but also participates in defending against fungi, protozoans, cancers, 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.

## Overview

CD4$^+$ T-helper cells may be differentiated into two main categories:
* T$_H$1 cells which produce interferon gamma and lymphotoxin alpha,
* T$_H$2 cells which produce IL-4, IL-5, and IL-13.
A third category called T helper 17 cells (T$_H$17) were also discovered which are named after their secretion of Interleukin 17.
CD8$^+$ cytotoxic T-cells may also be categorized as:
* T$_c$1 cells,
* T$_c$2 cells.
Similarly to CD4$^+$ T$_H$ cells, a third category called T$_C$17 were discovered that also secrete IL-17.
As for the ILCs, they$^{[Clarificationneeded.]}$ may be classified into three main categories
* 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.
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 cells by IL-15. CHILp cells may be induced to differentiate into ILC1 cells by IL-15, into ILC2 cells by IL-7 or ILC3 cells by IL-7 as well.
T-cell progenitors may differentiate into naïve CD8$^+$ cells or naïve CD4$^+$ cells. Naïve CD8$^+$ cells may then further differentiate into T$_C$1 cells upon IL-12 exposure, [IL-4] can induce the differentiation into T$_C$2 cells and IL-1 or IL-23 can induce the differentiation into T$_C$17 cells. Naïve CD4$^+$ cells may differentiate into T$_H$1 cells upon IL-12 exposure, T$_H$2 upon IL-4 exposure or T$_H$17 upon IL-1 or IL-23 exposure.

## 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$_H$1, T$_C$1, and group 1 ILCS activate macrophages, converting them to potent effector cells. It provides defense against intracellular bacteria, protozoa, and viruses. It is also responsible for inflammation and autoimmunity with diseases such as rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease all being implicated in type 1 immunity. Type 1 immunity consists of these cells:
* CD4+ T$_H$1 cells
* CD8$^+$ cytotoxic T cells (T$_c$1)
* T-Bet$^+$ interferon gamma producing group 1 ILCs(ILC1 and Natural killer cells)
CD4$^+$ T$_H$1 Cells
It has been found in both mice and humans that the signature cytokines for these cells are interferon gamma and lymphotoxin alpha. The main cytokine for differentiation into T$_H$1 cells is IL-12 which is produced by dendritic cells in response to the activation of pattern recognition receptors. T-bet is a distinctive transcription factor of T$_H$1 cells. T$_H$1 cells are also characterized by the expression of chemokine receptors which allow their movement to sites of inflammation. The main chemokine receptors on these cells are CXCR3A and CCR5. Epithelial cells and keratinocytes are able to recruit T$_H$1 cells to sites of infection by releasing the chemokines CXCL9, CXCL10 and CXCL11 in response to interferon gamma. Additionally, interferon gamma secreted by these cells seems to be important in downregulating tight junctions in the epithelial barrier.
CD8$^+$ T$_C$1 Cells
These cells generally produce interferon gamma. Interferon gamma and IL-12 promote differentiation toward T$_C$1 cells. T-bet activation is required for both interferon gamma and cytolytic potential. CCR5 and CXCR3 are the main chemokine receptors for this cell.
Group 1 ILCs
Groups 1 ILCs are defined to include ILCs expressing the transcription factor T-bet and were originally thought to only include natural killer cells. Recently, there have been a large amount of NKp46$^+$ 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 IL-2 in response to cytokine stimulation but have low or no cytotoxic ability.