30 Lymphocytes and their role in Innate and Adaptive Immunity

Lymphocytes

Lymphocytes are white blood cells (WBCs, leukocytes) that play an important role in providing immune defense.  There are 3 major types of lymphocytes: natural killer (NK) cells, T cells, and B cells.  All lymphocytes have large nuclei and little cytoplasm, making them distinguishable under the microscope from other WBCs.  Lymphocytes make up 20-30% of circulating WBCs.

Natural Killer Cells provide an important function in the innate (non-specific) immune system as they are able to destroy many types of abnormal cells (e.g. virally-infected cells and cancerous cells).  NK cells contain granules filled with toxins which are used to either induce apoptosis or lysis of abnormal, infected and cancerous cells.  Please read the previous section for more information on NK cells.

T and B Cells:

Both T and B cells play important roles in adaptive (specific) immune response.  Once activated, T cells can attack various pathogens, such as E. coli or Staphylococcus spp. based on the ability to identify and bind to specific foreign antigens on the surface of these pathogens, and then implement pathogen destruction.  B cells provide protection by producing antibodies which will specifically bind to foreign antigens of pathogens and either inactivate the pathogens or target them for destruction by WBC phagocytes.  The foreign (also known as non-self or exogenous) antigens that immune system cells target are usually parts of pathogens (e.g. proteins, peptides, lipids, polysaccharides, or nucleic acids).

Even though lymphocytes circulate the bloodstream (especially the NK cells), most B and T lymphocytes are inactive and and as their name, lymphocyte, suggests are located in lymphoid tissues (e.g. tonsils, spleen, lymph nodes, thymus and bone marrow).  From a cardiovascular circulation point of view, this is a convenient arrangement as the lymphatic system is contantly collecting excess fluid from tissues throughout the body via blind-end capillaries and passing that lymph fluid through lymph nodes for screening by B and T lymphocytes before returning it to the blood stream’s circulation.  Within the lymph nodes, B cells are located in the cortex, while T cells are found in the medulla which is ideal for screening lymph fluid for pathogens.

Other lymphatic tissues (e.g. tonsils, GALT Gut-Associated Lymphoid Tissue including Peyer patches and the appendix) are strategically located just under the mucosal linings of the digestive tract which is a potential portal of entry for pathogens, making this another excellent location for B and T cells.  Within the bone marrow and spleen, B and T lymphocytes are also able to screen for any pathogens within the blood stream, lymph fluid and tissues.

T cells (Thymus cells, Thymocytes): provide cell-mediated immunity.  T cells are able to recognize and then generate attacks against specific pathogens based on presence of pathogenic antigens that are foreign or “non-self”.   T cells arise from hematopoietic cells in the bone marrow.  Immature T cells migrate to the thymus where they are subjected to hormones and different cytokines and mature as they pass from the thymic cortex on the way to the medulla.  In the cortex, the maturing T cells that express a functional T Cell Receptor (TCR) are nurtured, whereas those that lack a functional TCR go through apoptosis, in a process called death by neglect.  Each mature thymocyte expresses a unique TCR.  The TRC+ T cells then begin to express either CD8 receptors or CD4 receptors as they enter the thymic medulla. Within the medulla, positive selection takes place for both CD4+ T cells and CD8+ T cells.

For CD4+ T cells, during positive selection, the CD4+ T cells that weakly bind Major Histocompatibility Complex, MHC Class II (self cell surface) molecules mature to become CD4+ Effectors (Helper T cells).  In this selection process, both the TCR and the CD4 co-receptor are required to bind MHC II.   The CD4+ T cells that strongly bind self MHC II undergo apoptosis.  If these cells did not undergo apoptosis they could become involved in autoimmunity.  The CD4+ T cells that moderately bind self MHC II become CD4+ Regulatory T Cells which are thought to play a role in immunosuppresion as well as in preventing autoimmunity.   Regulatory T cells suppress and downregulate the proliferation of Effector T cells, while CD4+ Effector Helper T cells play an important role in adaptive immunity and protection against pathogenic infection.

In a similar process, for CD8+ T cells, during positive selection, the CD8+ T cells that weakly bind MHC Class I (self cell surface) molecules mature to become CD8+ Effectors (Cytotoxic T cells).  In this selection process, both the TCR and the CD8 co-receptor are required to bind MHC I.   The CD8+ T cells that strongly bind self MHC I undergo apoptosis.  If these cells did not undergo apoptosis they could become involved in autoimmunity.  The CD8+ T cells that moderately bind self MHC I become CD8+ Regulatory T Cells which are though to play a role in immunosuppresion as well as in preventing autoimmunity.   Regulatory T cells suppress and downregulate the proliferation of Effector T cells, while C84+ Effector Cytotoxic T cells play an important role in adaptive immunity and protection against pathogenic infection.

Note:  MHC are also known as HLA (Human Leukocyte Antigens).

Role of CD8+ T Cells in Providing Specific Immunity:

1. CD8+ Effectors (Cytotoxic T cells, CD8 cells, or T_C cells):  CD8 cells are very important in destroying cancerous cells as well as infectious agents (e.g. bacteria, viruses, fungi).  The steps that occur in this type of protection against pathogens are as follows.
   1. When a host cell becomes infected by a virus or intracellular bacteria, the infected cell is often able to gather antigens from the infecting pathogen to bind to MHC-1 complexes.
   2. The MHC-I complexes translocate to the plasma membrane and display the foreign antigens on the surface of the cell.  Cancerous or abnormal cells sometimes display atypical antigens that at times can be recognized by CD8 cells.
   3. CD8 cells have unique T cell receptors (TCRs) and when an infected cell (or cancerous cell) presents with an antigen that binds to the TCR and CD8 co-receptor, the CD8 cell is rapidly activated.  It releases cytokines to recruit macrophages and NK cells and also begins to proliferate and produce 2 types of daughter cells that differentiate and become active.  The daughter CD8 cells include:  short-lived CD8+ Effectors (Cytotoxic T cells, CD8 or T_C cells), and Memory T_C cells.
   4. The CD8+ Effectors (Cytotoxic T cells) daughter cells then circulate the bloodstream and infected areas binding to foreign antigens and destroying infected cells and pathogens by either inducing apoptosis or by secreting toxins that cause the abnormal cell to lyse.  Cytotoxic T cells can release perforin, granzymes, and other toxins that create portals in the affected cell, which then swell with water and burst in a process known as osmotic lysis (or cytolysis).  This is sometimes called a ‘Search and Destroy Mission’.  After the infectious agent is removed, a few CD8+ Effector cells may persist and differentiate into memory CD8+ T cells.
   5. The antigen memory and robustness of the CD8+ Memory T cell pool is ensured, by having CD8+Memory T cell proliferation rates that balance their apoptotic rates.  In this way, pools of young healthy CD8+ Memory T cells continue to carry the pathogen antigen memory for up to 10 years or more and are able to mount a faster CD8+ T cell response to the same pathogen upon re-exposure in comparison with the primary response.
   6. A secondary response (re-exposure to a pathogen) is characterized by CD8+ Memory T cells quickly ramping up proliferation to produce both Cytotoxic T cells (that perform a Search and Destroy Mission to remove the pathogen) and more CD8+ Memory T cells.

Role of CD4+ T Cells in Providing Specific Immunity:

1. CD4+ Effectors (Helper T cells, CD4 cells, or T_H cells):  CD4 cells are very important in stimulating the activation of B cells and CD8+ (Cytotoxic) T cells as well as in the activation of macrophages of neutrophils.  Helper T cells play a crucial role in orchestrating the destruction of infectious agents (e.g. bacteria, viruses, fungi).  The steps that occur in this type of protection against pathogens are as follows.
   1. When a pathogen is phagocytosed by an Antigen-Presenting Cell (APC, e.g. a macrophage, dendritic cell or B cell), the pathogen’s antigens are bound to MHC Class II molecules and then displayed on the cell surface of the APC.  In this manner, pathogenic antigens are presented to Helper T cells. Often dendritic cells will travel from the infection site to the lymph nodes in order to activate Helper T cells.
   2. Helper T cells ahve unique T cell receptors (TCRs).  The Helper T cells that possess the TCRs and CD4 co-receptors that bind to the pathogenic antigen that has been presented by the APC become activated.  Typically the APC also releases cytokines (e.g. monokines) to ensure the activation of the bound Helper T cell.
   3. Once activated, the Helper T cell proliferates to produce 2 types of daughter cells that differentiate and become active, CD4+ Effectors (Helper T cells, CD4 or T_H cells), and Memory T_H cells.
   4. The CD4+ Effectors (Helper T cells) then activate both CD8 cells and B cells (that have already been sensitized by exposure to the pathogenic antigen).   In response both CD8 cells and B cells proliferate.  Daughter CD8 cells embark on Search and Destroy Missions and daughter B cells called Plasma cells produce antibodies that circulate the bloodstream and bind to the pathogenic antigen.   When the B cells are stimulated to proliferate by Helper T cells, daughter B Memory cells are also produced.
   5. In similar manner to CD8+ Memory T cells, the antigen memory and robustness of both the CD4+ Memory T cell and Memory B cell pools are ensured, by having proliferation rates that balance their apoptotic rates.  In this way, pools of young healthy CD4+ Memory T and Memory B cells continue to carry the pathogen antigen memory for up to 10 years or more and are able to mount a faster CD4+ T cell and B cell responses to the same pathogen upon re-exposure than the primary response.
   6. A secondary response (re-exposure to a pathogen) is characterized by CD4+ Memory T cells quickly ramping up proliferation to produce both Helper T cells (that activate CD8 cells and B cells and therefore antibodies) and CD4+ Memory T cells.

B cells (Bone-derived cells): arise from the daughter cells of hematocytoblasts (hematopoietic stem cells) in the bone marrow, which is considered a primary lymphatic tissue.  Once mature, B cells travel the bloodstream to the spleen for further maturation and then while many B cells remain in the spleen, others travel to other secondary lymphatic tissues (e.g. tonsils, spleen, lymph nodes, and thymus) as well as the bone marrow.

Role of B Cells (B Lymphocytes) in Providing Specific Immunity:

1. B cells are capable of phagocytosing pathogens and displaying their antigens using MHC Class II molecules..  A B cell that has been sensitized in this manner can be activated by a Helper T cell that has a TCR that is able to bind to the pathogen antigen that has been displayed on the surface of the B cell.  The bound Helper T cell can then activate the B cell which proliferates to produce 2 types of daughter cells:  Plasma cells that secrete antibodies against specific pathogens, and Memory B cells for long-term immunity.

Summary:

• T cells include cytotoxic T cells, helper T cells, suppressor T cells, and memory T cells, each playing specific roles in immune responses.
• Cytotoxic T cells embark on Search and Destroy missions finding and destroying pathogens based on specific antigens.
• Helper T cells activate cytotoxic T cells and B cells, while suppressor T cells regulate immune responses to prevent overactivity.
• Helper T cells are activated by APCs presenting antigens on MHC II to them, followed by the release of cytokines.
• B cells called plasma cells produce antibodies.
• Antibodies inactivate pathogens and also act as opsonins enabling WBCs to phagocytose pathogens.
• Antibodies have various functions, including neutralizing toxins, preventing viral infection, agglutinating pathogens, and promoting phagocytosis.
• Pools of Memory T cells and Memory B cells remain in the body for years, providing rapid responses upon re-exposure to pathogens.
• Memory B cells quickly respond to re-infection by producing antibodies specific to previously encountered pathogens.
• Vaccination stimulates the production of memory B and T cells, resulting in a faster and more effective immune response upon subsequent exposure to pathogens.
• Cytotoxic T cells destroy pathogens by creating perforin portals, releasing lymphotoxin, or inducing apoptosis in infected cells.
• During infection, neutrophils are the first responders, followed by natural killer cells, macrophages, and lymphocytes, leading to a specific immune response.