Types of Memory T cells and their mode of action

In this article, I briefly describe the different types of memory T cells and their mode of action, along with several surface proteins they express.

Table of Contents

Memory T cells

In a secondary lymphoid organ, in the zone of T cells, when a T cell is engaged with a dendritic cell for one or two days, it results in the enlargement of a naïve T cell into a blast cell, which undergoes repeated rounds of cell division.

A naïve T cell proliferates with the effect of many signals into activated T cells. These activated T cells undergo two to three divisions per day, generating a clone of progeny cells. Gradually activated T cells and their progeny get functional abilities and become effector cells and memory cells.

Effector cells are called as cytotoxic T cells, and each subset of effector T cells plays a precise and vital role in the immune response. Memory cells are long-lived. These are responsible for a stronger and more agile response to any infection by the same pathogen in the future.

Naïve T cells can live for months, whereas effector cells are short-lived, i.e., from a few days to a few weeks. However, memory T cells are long-lived and can extend their lives by dividing while present in an organism.

The activation of T cells results in the proliferation and generation of effector cells. When the pathogen gets cleared, then about 90% of effector cells undergo apoptosis. However, the diminishing of effector cells is not the end of T cells because antigen-specific memory T cells are quiescent and long-lived than effector T cells. These memory T cells represent about 35% of circulating T cells in a healthy young adult, which is 60% in an old individual.

Mode of action of memory T cells

Memory T cells, when come across again with the same antigen, give an elevated secondary response than the previous one. The secondary immune response is more sturdy and effective than the primary one.

Memory T cells are typically in the G₀ stage of the cell cycle and generate their energy from lipids through oxidative phosphorylation. These cells get activated by macrophages, dendritic cells, and B cells, unlike naïve T cells, which get activated only by dendritic cells.

Memory cells can have an effective interaction with antigen-presenting cells by the expression of different patterns of surface adhesion molecules and co-stimulatory receptors. Memory cells quickly respond and show higher sensitivity towards stimulation. The recirculation patterns of memory cells, differ from naïve and effector T cells. Some memory cells stay in the lymph nodes and other secondary lymphoid organs for a long time, some circulate in tissues, and some stay in peripheral organs.

Memory T cells can be distinguished as:

Central memory T cells (T_CM)

2. Effector memory T cells (T_EM),

3. Resident memory T cells (T_RM),

4. Stem cell memory T cells (T_SCM).

T cells show different surface protein expression

There are generally four surface markers expressed by T cell subsets in mice, which distinguish between naïve, effector, and memory T cells. The four surface markers are CD44, CD69, CCR7, and CD62L, which are expressed differently in the T cell subsets.

The surface marker CD62L is an adhesion protein that directs the T cells to the secondary lymphoid organs like lymph nodes or spleen. Naïve T cells express high levels of CD62L and are directed towards lymph nodes or spleen.

The elevated expression of CD44 by memory T cells

The increased expression of surface marker CD44 shows the response to the TCR-mediated activated signals. Thus, naïve T cells express low levels of CD44, showing their inactivated state. The effector helper and cytotoxic T cells express high levels of CD44. As they have TCR-mediated activated signals and low levels of CD62L, they are prevented from getting into secondary lymphoid organs and allowed to enter the infection sites in the periphery.

Memory T cells express high levels of CD44, reflecting that they have received signals through their TCR. The surface marker CCR7 is a chemokine receptor that directs the T cells toward secondary lymphoid organs. Central memory cells (T_CM) express CD62L and CCR7 and thus stay in secondary lymphoid organs.

Surface markers expressed by T_EM and T_SCM

The effector memory cells (T_EM) found in a variety of tissues express CD62L but do not express CCR7, showing their stay in non-lymphoid tissues. The surface marker CD69 is a C-type lectin that prevents T cells from leaving a tissue. The resident memory cells (T_RM) express CD69, which prevents the memory cells from leaving a tissue.

The memory T cells with stem cell potential (T_SCM) are the least differentiated memory cells, which express low levels of CD44 and high levels of CCR7 and CD62L like naïve T cells. The T_SCM also expresses CD95 and CD122 markers associated with memory cells.

Where do memory T cells reside, and what is their mode of action?

Different types of memory cells differ in their residing place and the mode of action. The central memory T cells (T_CM) live longer and reside in secondary lymphoid tissues.

The T_CM cells can undergo more divisions than the T_EM cells and generate a high amount of cytokine IL-2. However, they secrete a very low amount of other effector cytokines. Whenever the T_EM cells come across again with an antigen, they get highly activated and can differentiate into a variety of effector T cell subtypes.

The effector memory T cells (T_EM) circulate in peripheral tissues like skin, lungs, liver, and intestine, and unlike the T_EM cells, secrete low levels of cytokine IL-2 but high amounts of other effector cytokines. They play vital roles in responding early to re-infections.

The resident memory T cells (T_RM) respond to re-infections better than the T_EM cells and T_CM cells. It is because they always respond when come across a re-infection. The CD8⁺ T_RM cells are the best-defined resident memory T cells found in multiple tissues like the skin, mucosa, and brain. The CD4⁺ T_RM cells are found in multiple tissues involving the lungs and bone marrow. They are not easily located but circulate more readily than the CD8⁺ T_RM cells.

Stem cell memory T cells can develop into all other memory T cell subsets. They are found in secondary lymphoid tissue. The T_SCM possesses a self-renewing nature and renders an enduring source of T cells.

Emergence of memory cells

In secondary lymphoid tissue, naïve CD4⁺ and CD8⁺ T cells grow vigorously during the first few days of the immune response. But only a small part of the progeny of a naïve T cell commit to memory cell lineages. A progressive and linear model of development says that naïve T cells give rise to a small number of memory stem cells. Most of them proliferate to form central memory cells, which keep on proliferating to differentiate into effector memory cells.

Most of the effector memory cells differentiated terminally into effector cells. This mode of development shows the fact that the life span of memory subsets and stem cell capacity consistently decreases from the T_SCM(memory T cells with stem cell potential) to the T_CM (Central memory T cells) to the T_EM (Effector memory T cells). The effector memory T cells are the shortest-lived memory population with minimal or no self-renewal capacity. The resident memory T cells may arise from either the T_CM or T_EM.

With the help of T cells, the generation of the CD4⁺ and CD8⁺ memory T cells takes place. The better memory response depends upon the proliferation of a naïve lymphocyte after activation. Some cytokines like IL-7 and IL-15 may help to generate and maintain the T_SCM cells. IL-2 plays an important role in generating the effector memory T cells. More proliferation creates a better memory pool of T cells.

Disparity between the CD8⁺ and CD4⁺memory T cells

The CD8⁺ memory T cells proliferate more vigorously than the CD4⁺ memory T cells. Thus, they are present more in number than the CD4⁺ memory T cells. The CD8⁺ memory T cells have longer life spans than the CD4⁺ memory T cells. Both express different homing receptors and populate several layers of our barrier tissues.

In the epithelial layers, the CD8⁺ memory T cells are found in the epidermis of the skin and epithelium of the gut. The CD4⁺ memory T cells are found in deeper layers like the dermis of the skin and epithelium of the gut. The CD4⁺ memory T cells are more mobile than the CD8⁺ memory T cells.

Conclusion

There are mainly four types of memory T cells. They are central memory T cells, effector memory T cells, resident memory T cells, and stem cell memory T cells. The stem cell memory T cells are the least differentiated among all. They are found in secondary lymphoid tissue and can develop into all other memory T cell subsets.

Memory cells quickly respond and show higher sensitivity towards stimulation. Memory T cells differ in their residence along with their mode of action. The CD8⁺ memory T cells have a more vigorous proliferative capacity than the CD4⁺ memory T cells.