Lymphocyte Development and Activation

• Lymphocytes develop and are activated

Lymphocyte Production

• Lymphocytes originate from the same pluripotent stem cells (PPSCs) in bone marrow, but do not pass through the myeloid stem cell stage
• Lymphoid stem cells develop into lymphocytes
• Lymphocytes move to primary (central) tissues to receive antigen receptors
• Lymphocytes move to secondary (peripheral) tissues to await antigen stimulation
• Lymphoblasts are "reactive lymphocytes" responding to antigen stimulation
• Lymphocytes mature in the bone marrow in 2 to 5 days
• After initial formation in bone marrow, lymphocytes leave and enter primary (central) lymphoid tissues for further development before settling into their permanent homes in secondary (peripheral) lymphoid tissues

Lymphoid Tissues

• Primary lymphoid tissues, also known as central lymphoid tissues, include the thymus gland, where T cells develop, and the bone marrow, where B cells develop
• Gut-associated lymphoid tissue (GALT) is also a primary lymphoid tissue for B cells
• Secondary lymphoid tissues, also known as peripheral lymphoid tissues, include lymph nodes, the spleen, GALT (both primary and secondary), tonsils, Peyer's patches, and the appendix (in humans)

Lymphocyte Morphology

• Small and large lymphocytes may be observed on differential
• Small lymphocytes are smaller than other white blood cells (WBCs), have a spherical nucleus, and a variable amount of homogenous, sky-blue cytoplasm
• Large lymphocytes may be as large as granulocytes, have a spherical nucleus, and more cytoplasm than small lymphocytes
• Reactive lymphocytes, also known as lymphoblasts, undergo antigenic stimulation
• They are medium to large in size and have more cytoplasm than typical lymphocytes
• The cytoplasm often exhibits increased basophilic staining, but can be pale blue
• Vacuoles and/or azurophilic granules may be present, and the nucleus may be round, elliptical, indented, cleft, or folded
• Chromatin is often less dense, with one or two nucleoli

Lymphocytes - General Information

• Lymphocytes are the predominant white blood cell (WBC) in circulation in ruminants, swine, and many laboratory animals
• Lymphocytes are the only WBCs that do not have phagocytic ability
• Most lymphocytes remain in lymphoid tissues and can recirculate between these tissues and the bloodstream

Lymphocyte Life Span

• Lymphocytes live the longest of all blood cells, with some surviving as long as 20 years
• Provide permanent immunity

Lymphocyte Functions

• Primary cellular component of lymph fluid
• Initiate and execute immune responses
• Cell-mediated immunity: T lymphocytes
• Humoral immunity: B lymphocytes

Types of Lymphocytes

• T lymphocytes (T cells)
• B lymphocytes (B cells)
• Natural killer lymphocytes (NK cells) also known as null cells

T Lymphocytes: Cell-Mediated Immunity

• 70% of lymphs observed on differential are T cells
• They are responsible for cell-mediated immune response (CMIR) and do not produce antibodies (Ab)
• They may directly destroy cells that have antigens (Ag) on their surface and also work against protozoa, fungi, and some helminths
• T cells leave the bone marrow and are processed in the thymus before moving to peripheral lymphoid tissue, and they can recirculate through blood and lymph
• Before T cells can act, macrophages (antigen-presenting cells or APCs) must first process the antigen
• The macrophage phagocytizes the antigen and displays it to the T cell, which is then sensitized
• These sensitized T cells undergo blast transformation (reactive lymphocyte/lymphoblast) and mitosis
• Over the course of several days, five types (or colonies) of T cells are produced

Types of T Cells

• T Helper (TH) cells are the most numerous and are immunoregulatory
• Through the production of lymphokines, the TH cells "turn on" B cells, enhancing their development and stimulating plasma cells to make immunoglobulins (Ig); they also "turn on" Tc cells and Tr cells
• TH cells are extremely important in the immune response, and immunodeficiency viruses selectively destroy them
• T Regulatory (TR) cells (sometimes called T Suppressor cells) are also immunoregulatory and are the second most common type
• TR cells "turn off" TH cells to prevent them from adversely affecting host tissue, Tc cells when their function is no longer necessary, and plasma cells when immunoglobulin is no longer needed
• T Cytotoxic (Tc) cells (sometimes called T Killer cells) destroy cells with antigens on their surface
• They are non-phagocytic, but can attach to an antigenic cell, rupture its membrane, and destroy it, then move on to the next infected cell
• T Delayed Hypersensitivity (TD) cells (sometimes called T Mediator cells) respond inappropriately to antigenic stimulation
• They are associated with type IV or delayed hypersensitivity reactions and are involved when the immune system responds inappropriately to antigenic stimulation with an allergic or hypersensitivity reaction
• T Memory (TM) cells are a clone of the original T cell and are the most numerous lymphocytes circulating in the peripheral blood
• They respond to a specific antigen at a later time and are primed for rapid response when re-exposed to their specific antigen, thereby providing longer term immunity

B Lymphocytes: Humoral Immunity

• B lymphocytes, which are B cells, make up 20% of lymphocytes seen on a differential, and most B cells remain in peripheral lymphoid tissue
• They are responsible for the humoral immune response and produce immunoglobulins (Igs), which are antibodies (Abs)
• Each immunoglobulin is made against a specific antigen (Ag)
• B cells are processed in the bone marrow or, after leaving the bone marrow and moving into GALT, before moving to peripheral lymphoid tissue
• Before B cells can act, a macrophage (APC) must first process the antigen
• The macrophage phagocytizes the antigen and displays it to the B cell, which is then sensitized
• These sensitized B cells undergo blast transformation (reactive lymphocyte or lymphoblast) and mitosis, and over the course of several days, two types (or colonies) of B cells are produced
• B Memory cells are from a clone of original B cells
• They are responsible for the secondary (anamnestic) response
• B memory cells are ready to act (transform into plasma cells to produce and release immunoglobulin) when the host is re-exposed to the original antigen, eliciting a more rapid, potent, and long-lasting response

Types of B Cells

• B Memory cells
• Plasma cells with the assistance of TH cells

Plasma Cells

• Plasma cells are extremely rare in peripheral blood
• They have a small, clear area in the cytoplasm near the nucleus; a small, eccentric nucleus with clumped chromatin; and abundant, highly basophilic cytoplasm
• Produce immunoglobulins (Igs; aka antibodies or Ab) in response to Ag stimulation which are secreted directly into plasma and seek out and destroy more of the same Ag that initiated their production

Immunoglobulins

• IgM: The first immunoglobulin to appear after exposure to a specific antigen (i.e., "primary response") and continues to be produced during first and subsequent exposures (though in lesser amounts) to same Ag
• It is a large molecule that remains in the bloodstream and is produced relatively quickly, taking 7 to 10 days for a plasma cell to produce significant quantities
• IgM may respond quickly enough to prevent illness in the animal and enhances phagocytosis (especially of microorganisms) by neutrophils and monocytes/macrophages
• IgG is the second immunoglobulin to appear upon exposure to a specific antigen and is also produced during first and subsequent exposures (in greater amounts) to same Ag
• It is a small molecule that can leave the bloodstream and enter tissues
• IgG production is relatively slow, taking about 21 days, and an animal may become ill before the immune response can conquer the antigen
• IgG enhances phagocytosis by neutrophils and monocytes/macrophages and neutralizes toxins and viruses
• IgG can cross the placenta and into colostrum to confer natural passive immunity to the fetus
• IgA leaves the blood and enters tissue fluids (mucus, saliva, tears, colostrum)
• IgA confers a crucial role in passive immunity conferred to neonates through ingestion of colostrum
• IgE is associated with the allergic response and binds to mast cells and basophils in the presence of an antigen, thereby stimulating the release of histamine and heparin
• IgD's function is unknown, but it may serve as an antigen receptor on the surfaces of B cells

Natural Killer Cells

• Natural killer cells, also known as null cells or NK cells, are neither T cells nor B cells
• They comprise approximately 10% of lymphocytes seen on a differential and are part of the non-specific (innate) second line of defense because they do not have to be activated by an antigen
• They are not phagocytic, and must directly contact cells to lyse them
• They can destroy some tumor cells, cells infected with certain viruses, and some parasites (along with eosinophils)

Lymphocytosis

• Fear/excitement
• Persistent antigen
• Lymphosarcoma (LSA)
• Lymphoblastic leukemia
• Puppies and kittens

Lymphopenia

• Corticosteroids/stress
• Destruction of lymphoid tissue by viruses
• Chylothorax
• Immunosuppressive drugs/radiation

Acquired T cell deficiency

• Feline leukemia virus (FeLV)
• Feline Immunodeficiency Virus (FIV)