Contraction of our immune response and the response of effector and memory lymphocytes

In this article, I briefly explain the response of effector and memory lymphocytes to contraction of our immune response.

Table of Contents

Factors regulating the contraction of lymphocyte

In an immune response, lymphocytes can expand and increase in number up to a thousand fold. After the period of expansion, their number is suddenly decreased during the contraction period. At the end of the contraction period very less number of lymphocytes, i.e., nearly 5%-10% of lymphocytes remain and most of which are central and effector memory cells.

Lymphocyte contraction is regulated by both cell-extrinsic and cell-intrinsic factors. The immune cells have a certain life span. To maintain their survivability, most immune cells have to depend upon the external stimulation.

The neutrophils, memory cells, and effector T cells widely vary in their half-lives. The neutrophils have half-lives as hours. The effector T cells have half-lives, varying for 2-3 days, whereas memory cells have half-lives of decades.

Antigens and cytokines like IL-2, IL-7, and IL-15 act as stimuli as they aid in the survivability of effector cells. After clearing of an infection, cells compete among themselves to access stimuli as these become scanty.

Effector cells die as a result of withdrawal of these stimuli. Thus, they can’t produce signals, which leads to cell-intrinsic apoptosis. The apoptosis is triggered by shifting the balance between pro-survival and pro-death Bcl-2 members.

Research about T cells undergoing apoptosis during an immune response stresses upon the fact that antigen accessibility is vital for maintaining T cell survivability.

During an immune response antigen initiate to disappear within 5-8 days, causing the T cell numbers to decrease too. During the contraction phase, T cells could be saved by re-stimulation with antigen. It is also observed that, the CD4⁺ T cells contract rapidly than the CD8⁺ T cells.

Activation-induced cell death

In certain conditions, engagement of T cell receptor will elevate the expression of death receptor ligands like FasL. Activated T cells expressing FasL, engage Fas expressed on the surface of neighboring cells. As a result, cell-extrinsic apoptosis is set off, which is also known as activation-induced cell death (AICD).

According to some evidences, during a chronic infection when there is a high level of antigen, AICD operates to contract immune responses. T_H1 cells appear more vulnerable to activation-induced cell death.

Lymphocyte numbers are reduced by withdrawal of stimuli and activation-induced cell death, thus triggering apoptosis. The interactions, which inhibit proliferation cause the contraction of immune effector cells. Activated T cells elevate co-inhibitors like CTLA-4 and PD-1 later in the immune response.

CD28 binds to CD80/86 and CTLA-4 competes with CD28 for binding with CD80/86. CTLA 4 emits inhibitory signals to the T cell. The binding of PD-1 to PD-L2 on the surface of antigen presenting cells also emit inhibitory signals. These signals block the proliferation of T-cell and secretion of cytokines.

Activity of T cell also comes to an end by the inhibitory cytokines like IL-10 and TGF-β. The cytokines IL-10 and TGF-β are released by the T_REG cells (Regulatory T cells).

Thus, a combination of pro-apoptotic and antiproliferative influences brings about contraction. The contraction is brought by reducing the numbers of effector cells by 95%. Thus, after 10-14 days of initiation of the adaptive immune response, the ambience of the lymph node returns back to their naïve antigen state.

The effector cells exit the lymph node through efferent lymphatics and enter into other tissues to combat infection. In the lymph node, some central memory cells remain and other memory cells like effector memory and resident memory cells enter into other tissues.

The response of effector and memory lymphocytes

Most of the effector and memory lymphocytes exit secondary lymphoid tissues and circulate in the periphery. Their stay period in the periphery, depends upon the signals they receive during activation, and the cells they interact during circulation.

Activated lymphocytes after escaping lymph node recirculate through several tissues

The activated lymphocytes after exit from the lymph node or spleen spread all around body. The plasma cells move to various sites depending upon the anti-isotype-antibody they produce. The plasma cells producing IgM antibodies, stay in the medulla of the lymph nodes and release antibodies into the efferent lymphatics.

The cells producing IgA antibodies return to the barrier tissues, like gut-associated and lung-associated lymphoid tissues. The cells producing IgG antibodies travel to the bone marrow.

The cytotoxic CD8⁺ T cells move to the site of infection where they kill infected cells expressing MHC class-I peptide complexes. The CD4⁺ T cells, which give signals for promotion of B cell and differentiation of CD8⁺ T cells, stay in the lymph node. They keep on stimulating differentiation of lymphocytes.

Other CD4⁺ T cells travel to infection sites to elevate the potential of tissue phagocytes to clear opsonized pathogen. Some effector CD4⁺ T cells also complete their differentiation or undergo functional changes at the infection sites.

The effector memory cells circulate in peripheral tissues throughout the body, whereas central memory cells remain in the secondary lymphoid tissue. The tissue-resident memory cells reside in tissues for long time period. They share functions with resident innate immune cells and give first respond to reinfection.

The resident memory cells are available in high concentrations in the barrier tissues. They constitute the intraepithelial lymphocytes of the gut and lymphocytes in the skin epidermis. The skin contains almost double T cells than blood, and most of the T cells are resident memory T cells.

Shifting of effector and memory lymphocytes towards peripheral tissues is regulated by adhesion molecules and chemokine receptors

The cell adhesion molecules and the chemokine receptors change their expression and control the movement of effector and memory lymphocytes between and within the tissues. Within the tissue, unique set of adhesion molecules are expressed by tissue microenvironments that attract certain subsets of effector cells.

The Effector cells and effector memory cells decrease the expression of CCR7 and CD62L. Thus, they do not move back to secondary lymphoid tissues. However, the expression of adhesion molecules and chemokine receptors are elevated by the effector cells. Thus, their movement to relevant tissues is regulated.

If the effector cells and effector memory cells are generated in a lymph node, which drains the skin, then expression of homing receptors are up regulated. As a result, the effector cells travel back to the skin.

The intracellular adhesion molecules (ICAMs) and E-selectin on dermal venules of the skin bind to cutaneous leukocyte antigen (CLA) and LFA-1, whose up-regulation is controlled by effector cells. An extra protein CD69, a lectin, which is up-regulated by the resident memory cells helps them to keep within tissues.

However, lymphocytes when generated in gut-associated lymph nodes, express high levels of the integrins α₄β₂ and CD11a/CD18. These integrins bind to mucosal vascular addressin cell adhesion molecule (MADCAM) and different intracellular adhesion molecules (ICAMs) on lamina propia venules of the intestine. The chemokine receptor CCR9 is expressed by cells moving to the gut mucosa, binds to CCL25 in the small intestine.

Conclusion

In an immune response, lymphocytes increase in number up to a thousand fold. After the period of expansion, their number is suddenly decreased during the contraction period.

Both cell-extrinsic and cell-intrinsic factors regulate the contraction of lymphocytes. A combination of pro-apoptotic and antiproliferative influences brings about contraction. Though apoptosis of T cells could be saved by antigenic re-stimulation but sometimes this antigenic engagement leads to activation induced cell death.

After exiting from lymph node or spleen, activated lymphocytes recirculate through several tissues. The movement of effector and memory lymphocytes between the tissues and within the tissues is regulated by cell adhesion molecules and chemokine receptors.