First-ever video that captured the process in which developing killer T-cells are tested by dendritic cells

For the first time ever, UT Austin researchers captured the process in which developing killer T-cells (purple and white) are tested by dendritic cells (yellow), and others, to see if they react to normal proteins from the body. This safety check insures that the T-cells don't harm normal cells in the body and cause autoimmune disorders. Credit: University of Texas at Austin

For the first time, immunologists from The University of Texas at Austin have captured on video what happens when T-cells – the contract killers of the immune system, responsible for wiping out bacteria and viruses – undergo a type of assassin-training program before they get unleashed in the body.

A new imaging technique that allowed for the videos, described today in the journal Nature Communications, holds promise for the fight against autoimmune disorders such as Type 1 diabetes.

One of the human body’s most potent weapons against many diseases is the T-cell, but in people with autoimmune disorders, T-cells also wreak havoc by mistaking normal cells for invaders and attacking healthy parts of the body.

T cells are generated in the Thymus and are programmed to be specific for one particular foreign particle (antigen).

Once they leave the thymus, they circulate throughout the body until they recognise their antigen on the surface of antigen presenting cells (APCs).

The T cell receptor (TCR) on both CD4+ helper T cells and CD8+cytotoxic T cells binds to the antigen as it is held in a structure called the MHC complex, on the surface of the APC.

This triggers initial activation of the T cells. The CD4 and CD8 molecules then bind to the MHC molecule too, stabilising the whole structure.

This initial binding between a T cell specific for one antigen and the antigen-MHC it matches sets the whole response in motion.

This normally takes place in the secondary lymphoid organs.

Figure 1. Interaction between T cell and dendritic cell

Signal Two

In addition to TCR binding to antigen-loaded MHC, both helper T cells and cytotoxic T cells require a number of secondary signals to become activated and respond to the threat.

In the case of helper T cells, the first of these is provided by CD28.

This molecule on the T cell binds to one of two molecules on the APC – B7.1 (CD80) or B7.2 (CD86) – and initiates T-cell proliferation.

This process leads to the production of many millions of T cells that recognise the antigen.

In order to control the response, stimulation of CD28 by B7 induces the production of CTLA-4 (CD152).

This molecule competes with CD28 for B7 and so reduces activation signals to the T cell and winds down the immune response. Cytotoxic T cells are less reliant on CD28 for activation but do require signals from other co-stimulatory molecules such as CD70and 4-1BB (CD137).

T cells must recognise foreign antigen strongly and specifically to mount an effective immune response and those that do are given survival signals by several molecules, including ICOS4-1BB and OX40.

These molecules are found on the T-cell surface and are stimulated by their respective ligands which are typically found on APCs.

Unlike CD28 and the TCR, ICOS, OX40 and 4-1BB are not constitutively expressed on T cells. Likewise, their respective ligands are only expressed on APCs following pathogen recognition.

This is important because it ensures T cells are only activated by APCs which have encountered a pathogen and responded. Interaction of the TCR with peptide-MHC in the absence of co-stimulation switches the T cells off, so they do not respond inappropriately.

Figure 2. Schematic of early T cell activation. The T cell encounters a dendritic cell (DC) bearing its cognate peptide in an MHC molecule, and binds the peptide-MHC though CD3 and CD4 or 8. Subsequently, co-stimulation occurs through DC-bound CD86, CD80, OX40L and 4-1BBL. This induces full activation and effector function in the T cell.

Signal Three

Once the T cell has received a specific antigen signal and a general signal two, it receives more instructions in the form of cytokines.

These determine which type of responder the cell will become – in the case of helper T cells, it will push them into Th1 type (cells exposed to the cytokine IL-12), Th2 (IL-4), or IL-17 (IL-6, IL-23). Each one of these cells performs a specific task in the tissue and in developing further immune responses.

The resulting cell population moves out to the site of the infection or inflammation in order to deal with the pathogen.

Other cells present at the tissue site of inflammation– such as neutrophils, mast cells, and epithelial cells – can also release cytokines, chemokines, short peptides and other molecules which induce further activation and proliferation of the T cells.

“T-cells have the daunting task of recognizing and fighting off all of the diverse pathogens that we encounter throughout our lives, while avoiding attacking our own healthy tissue,” said associate professor Lauren Ehrlich, one of the authors of the study. “

These cells mature in the thymus, an organ just above the heart, where they ‘get educated’ to not attack the body.”

Ehrlich and postdoctoral researcher Jessica Lancaster captured video of this educational process in a mouse thymus.

Using a pair of powerful lasers that fire in short pulses and scan through a slice of live tissue every 15 seconds to reconstruct the positions, movements and intracellular signaling of cells, they observed that as T-cells develop, other cells in the thymus help them to encounter all sorts of ordinary human proteins that, later on, the T-cells will need to ignore in order to avoid attacking other parts of the body.

The researchers learned more about how different types of cells work together in the thymus to perform the safety tests and, in the event a T-cell fails, trigger it to self-destruct.

For the first time ever, UT Austin researchers captured the process in which developing killer T-cells (purple and white) are tested by dendritic cells (yellow), and others, to see if they react to normal proteins from the body.

This safety check insures that the T-cells don’t harm normal cells in the body and cause autoimmune disorders. Credit: University of Texas at Austin

Ehrlich says studying T-cells with this new imaging technique holds promise for improvements for human health that will depend on a better understanding of what’s happening in the thymus.

For example, patients who received bone-marrow transplants endure weeks or months with suppressed immune systems and a higher risk for developing autoimmune disorders, and people with Type 1 diabetes have T-cells that often attack the cells in the pancreas that produce insulin.

More information: J. N. Lancaster et al, Live-cell imaging reveals the relative contributions of antigen-presenting cell subsets to thymic central tolerance, Nature Communications (2019). DOI: 10.1038/s41467-019-09727-4

Journal information: Nature Communications
Provided by University of Texas at Austin


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