Innate and Adaptive Immunity

Types ofAdaptiveImmunity

Cells and Tissues of the Immune

System

Lecture 2

OVERVIEW OF THE IMMUNE SYSTEM

Cells: lymphocytes, macrophages & monocytes, dendritic cells, granulocytes. All arise from pluripotent hematopoietic stem cells in bone marrow.

Organs: lymph nodes (found in various locations), thymus, spleen - these constitute the lymphoid organs

Thymus and bursa (bone marrow) are called central lymphoid organs

Peripheral Lymphoid Organs: Except lymph nodes, spleen, and tonsils, liver, intestine and skin are also

are also important parts of the immune system.

Hematopoiesis

Pluripotent

Lymphocytes

• B Cells• T Cells• NK Cells

Lymphocytes

Jacques Miller found that removal of thymus (thymectomy) from neonatal mice resulted in fewer lymphocytes and no antibody to sheep red blood cells (1962). Later on, in thymectomized animals, the ability to reject allografts and to mount delayed hypersensitivity responses was drastically reduced.

By the mid-1960s, immunologists were convinced that there were indeed two separate arms of the immune system: one dealing exclusively with the production of circulating antibodies (humoral immunity), and another that is involved in the delayed hypersensitivity-type reactions and graft rejections (cell-mediated immunity). To have a good immune response, both have to exist.

Origin of T Cells

Classes of Lymphocytes

• Do Not Express Classical Lymphocyte Markers

• Predominantly NK Cells (CD56)• Eliminate Tumor Cells and Virally

Infected Cells• Express Low Affinity FcRIII (CD16)• Using CD16 They Can Carry Out

ADCC• Reduction of MHC I Can Activate

Them

Null Cells (NK Cells)

A T Cell ?

A B Cell?

Immune Cells Can Be Analyzed by Flow Cytometry

B CellCD19+

T HelperCD4+

T CytotoxicCD8+

Phenotypic Markers to DistinguishLymphocyte Subsets

Naive Activated EffectorPhases of

LymphocyteActivation

T vs B Cells

T cells B cells

Ag receptor TCR related to Ig BCR is membrane-bound Igbut not Ig (plus accessory molecules)

Ag recognition in context of MHC can recognize Ag aloneon APC or accessory cells

Functional Th (helper) and subsets of B cells only subsets Tc (cytolytic) subtly different in function

Secrete Cytokines Ig (as Ab) and cytokines

When Become (proliferating) Become lymphoblasts, then activated lymphoblasts become plasma cells

• Mononuclear Phagocytes– Monocytes and Macrophages

• Dendritic Cells

Accessory Cells

• Functions– Phagocytosis– Antigen processing

and presentation (APCs)

– Activation of T cells

Monocytes and Macrophages

Origin and Development of Macrophages

MONOCYTES AND MACROPHAGES

Monocytes are immature macrophages; monos circulate in blood & accum-ulate at sites of inflammation. Macrophages may differentiate in tissue inabsence of antigen (Kupffer cells in liver, e.g.) or differentiate in response toinflammation. They are Ag-presenting cells (APC). Also phagocytose microbes; contain bacteriocidal mechanisms.

macrophage in tissue, H&E stain

• mono in blood smear• Wright-Giemsa

Activated MacMonocyte

*Express CD14, a receptor for a wide variety of bacterial envelope molecules: LPS, components of bacterial cell walls. Ligation of CD14 leads to macrophage activation.

*Are activated by T cell derived cytokines such as interferons: leading to increased phagocytosis and microbicidal activity (increased activity of degradative enzymes, nitrogen and oxygen free radical production and prostaglandins etc.).

*Express receptors for Ab (FcR) and complement.

*Act as scavengers for apoptotic cells, cell debris and senescent cells (e.g., Kupffer cells in the liver bind "old" erythrocytes).

MONOS AND MACS CONTINUED

Dendritic Cells

• Transport Antigens to L. nodes• Initiation of T Cell Responses

Dendritic Cell Subsets

• Do Not Express MHC II Molecules

• Found in Lymph Follicles (Rich in B Cell)

• Express FcR For Antibodies and Complement

• Ag-Ab Complex Shown To Last Very Long (weeks to months)

Follicular DCs

(Myeloid DC)

Neutrophil

Eosinophil

Basophil

Granulocytes

Lymphoid Organs

• Primary (Generative) Lymphoid Organs– maturation site of

lymphoid cells– bone marrow, bursa

of Fabricius, thymus,

• Secondary Lymphoid Organs– efficient at trapping

and concentrating foreign substances

– site of Ag-driven proliferation and differentiation; e.g. Ab production

– spleen, lymph nodes, diffuse tissues, payers patch, tonsils

Organs Of Immune System

• Primary Lymphoid Organs– Bone Marrow and Thymus– Maturation Site

• Secondary Lymphoid Organs– Spleen, lymph nodes,– MALT (mucosal associated lymph

tissue)– GALT (gut associated lymph tissue)– Trap antigen, APC, Lymphocyte

Proliferation

ORGANS OF THE IMMUNE SYSTEM PRIMARY LYMPHOID ORGANS

Primary lymphoid organs are where lymphocytes arise and mature in the absence of antigenic stimuli. They are the bone marrow and thymus.

Bone marrow: Source of all hematopoietic progenitor (stem) cells, site of B cell maturation post-birth in mammals.

About 1 in every 10,000 to 15,000 bone marrow cells is thought to be a stem cell. In the blood stream 1 in 100,000 blood cells. Chicken Bursa

PRIMARY LYMPHOID ORGANS: THYMUS

Thymic epithelial cells are derived from the third pharyngeal pouch.

The thymus is the site where T cells develop.

It gradually enlarges during childhood but after puberty it undergoes a process of involution.

The thymus is arranged into an outer cortex and an inner medulla. Immature lymphoid cells in the cortex. Mature T cells are in the medulla from where mature T lymphocytes enter the circulation.

LYMPH NODES: filter lymphatic fluid; sites of Ag presentation & cell traffic

SECONDARY LYMPHOID ORGANS

Peripheral lymphoid organs: lymph nodes, spleen, tonsils, adenoids, and lymphoid tissue associated with other organ systems (gut, skin, mucosa).

Lymph nodes have a fibrous capsule from which trabeculae extend towards the center, forming a framework for the lymphatic parenchyma (cortex, paracortex, and medulla).

1 - cortex (B Cells) 2 - paracortical zone (T Cells) 3 – medulla(T, B, Mac) 4 - medullary cords 5 - lymphoid follicle of the cortex 6 - capsule 7 - subcapsular sinus 8 - cortical sinus 9 - medullary sinus

LYMPH NODES

LYMPH NODES, CONTINUEDFunctions of structural elements of lymph nodes

Subcapsular Sinus

Lymph afferent lymphatics, sinuses lined with macrophages efferent lymphatic (ultimately all drain into the portal vein).

Lymphocytes enter the node primarily from the blood via HEV efferent lymphatics.

DCs migrating from tissue enter the node into the T cell areas.

B cells entering nodes from blood must cross the T rich area in transit to the B cell rich areas thus optimizing T-B cooperation.

The spleen serves two major functions: *It is responsible for the destruction of old red blood cells (RBCs) - this occurs in the red pulp;*It is a major site for mounting the immune response - the white pulp. The spleen behaves like a lymph node, but instead of filtering lymph, it filters blood.Has the hematopoiesis function in mice.

SPLEEN      Stained with haematoxylin and eosin 1 - lymphoid follicle (white pulp) 2 - red pulp 3 - capsule 4 - trabeculae (connective tissue)

LYMPH NODES, CONTINUED

INSIDE THE SPLEEN

Red pulp

White pulp

Mouse splenic CD3 expression inperiarteriolar lymphocyte sheath of white pulp and in scattered cells in red pulp.

Lymphoid tissue found at the gastrointestinal tract, respiratory tract and urogenital tract.

MALT consists of aggregates of lymphocytes, macrophages, DCs, and other accessory cells.

MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT)

This is comprised of: * tonsils, adenoids (Waldeyer's ring) * Peyer's patches * lymphoid aggregates in the appendix and large intestine * lymphoid tissue accumulating with age in the stomach * diffusely distributed lymphoid cells and plasma cells in the lamina propria of the gut

GUT-ASSOCIATED LYMPHOID TISSUE (GALT)

SKIN-ASSOCIATED LYMPHOID TISSUE (SALT)

Skin is an active participant in host defense. It has the capability to generate and support local immune and inflammatory responses to foreign Ags that enter the body via the skin.

Cells of SALT include keratinocytes, Langerhans cells (immature DCs found in skin), intraepiethelial T cells, and melanocytes.

Langerhans cells form a continuous epidermal meshwork: they capture Ag, then migrate to draining lymph nodes, where they act as Ag-presenting cells.

(T Cell Progenitors)

Effect of Thymectomy?

Site of T Cell Maturation

Effect of Thymectomy in Adult

Circulation of Naïve and Activated/Memory T Lymphocytes

Activated/Memory Lymphocyte Circulation in pig?