T-cell development

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T-cell development

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T-cell development

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Interleukin-12, released from macrophages, induces the differentiation of T cells to cells.

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Content Reviewers:

Rishi Desai, MD, MPH

Your immune system is like the military - with two main branches, the innate immune response and the adaptive immune response.

The innate immune response is immediate and non-specific, meaning that although they distinguish an invader from a human cell, they don’t distinguish one invader from another invader.

The adaptive immune response is highly specific for each invader.

The cells of the adaptive immune response have receptors that differentiate one pathogen from another by their unique parts - called antigens.

These receptors can distinguish between friendly bacteria and potentially deadly ones.

This response takes days to weeks to become activated, but is also responsible for immunologic memory.

Now, the key cells of the adaptive immune response are the lymphocytes- the B and T cells -which are generated during lymphopoiesis.

Lymphopoiesis has three goals - to generate a diverse set of lymphocytes - each with a unique antigen receptor, to get rid of lymphocytes that have receptors that are self-reactive meaning that they’ll bind to healthy tissue, and finally to allow lymphocytes that aren’t self-reactive to continue maturing in secondary lymphoid tissue.

Normally, hematopoietic stem cells, within the bone marrow mature into a common lymphoid progenitor cell, which then becomes either a B-cell or a T cell.

To become a B cell, it has to develop into an immature B-cell in the bone marrow and then complete its maturation into an antibody secreting B cell, called a plasma cell, in the lymph nodes and spleen.

To become a T cell, it has to migrate to the thymus and become a thymocyte, where it completes its development into a mature T cell.

So, “B” for bone marrow and “T” for thymus.

In T cell development, the common lymphoid progenitor leaves the bone marrow and goes to the thymus, because that’s where the developing T cells or thymocytes mature.

The thymus is a fatty organ that sits in front of the heart, and as we age, much like our waistlines, the thymus get fattier and fattier.

This fat crowds out the space that used to be reserved for T cell development, and it’s one reason why cell mediated immunity declines over time - a process called involution of the thymus.

So the thymus has an outer cortex, and the inner medulla.

Within the medulla, there are epithelial cells which support the developing T cells as well as dendritic cells which present antigens to developing T cells on molecules called major histocompatibility complexes or MHC molecules.

That’s important because T cells have T cell receptors that can only bind peptide antigens if they’re displayed on an MHC molecule - which is sort of like a silver platter.

So if the T cell receptor can’t bind to the MHC molecule, then the T cell isn’t going to able to do its job.

So of course, a key element of T cell development is formation of this T cell receptor, which is made of two chains, an alpha chain which is like the light chain of a B cell receptor, and a beta chain which is like the heavy chain of a B cell receptor.

The alpha and beta chains are made up of gene segments called V for variable, D for diversity, and J for joining.

The beta chain includes 1 V segment, 1 D segment, and 1 J segment; while the alpha chain only contains 1 V segment and 1 J segment.

Every person inherits multiple copies of the V, D, and J segments, and they can be rearranged interchangeably to make a unique structure. A bit like how you might have several pairs of shoes, pants, and shirts and can create mix and match them to create lots of different outfits.

For the alpha chain, each person has between 70-80 variable gene segments and 61 joining J segments, and that’s just for the alpha chain!

There are more V,D, and J segments for the beta chain.

So one T cell might have a beta chain on it’s T cell receptor that has a V1-D3-J5 combination and an alpha chain that is V7-J2, and another T cell might have a beta chain that has a V44-D10-J1 combination and an alpha chain that is V2-J3 thus making completely different T cell receptors with completely different antigen specificities.

Now, to have a fully functioning T cell receptor, a T cell has to get through a series of successful gene rearrangements, first for the beta chain and then the alpha chain. And if the T cell fails at any stage, it dies!

T cell development is broken into three key stages based on which key molecules it is expressing on its surface at any given time.

These molecules, CD3, CD4, and CD8 are expressed in addition to the T cell receptor.

All T cells express the CD3 molecule which is part of the T cell receptor, and once the T cell is fully mature it will either express CD4 or CD8.

When the common lymphoid progenitor first arrives in the thymus it doesn’t express anything on its surface so it’s considered CD3-, CD4-, and CD8- and is referred to as a double negative stage or DN stage cell because it has neither CD4 or CD8 at this point.

The DN stage can be further broken down into DN1, DN2, DN3, DN4.

As the cell moves through the steps to create a functional T cell receptor it will then begin to express CD3 in addition to CD4 and CD8, all on the same cell.

The dual expression of CD4 and CD8 is why it’s called the double positive or DP stage.

Once the cell completes its expression of a functional T cell receptor it will continue to express CD3 but then will downregulate expression of either CD4 or CD8 and be known as a single positive T cell or SP.

Throughout all of these stages the T cell interacts with epithelial cells of the thymus which release growth factors as well as molecules like interleukin 7 and 2, called IL-7 and IL-2 for short, which makes these DN1 cells mature.