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1. Adaptive Immunity

2. Innate immunity includes barriers (skin), phagocytic cells, complement, and soluble mediators. It provides an immediate but non-specific defense. Adaptive immunity develops after exposure to pathogens. It is : Specific → targets particular antigens. Memory → remembers previous exposures for faster, stronger responses. Enhanced responses → more effective after repeated exposure. Types of adaptive immunity 1. Humoral immunity Mediated by B lymphocytes. Plasma cells produce antibodies that act in body fluids. Antibodies neutralize toxins, block pathogens, and help eliminate extracellular microbes. 2. Cell-mediated immunity (CMI) Mediated by T lymphocytes. Helper T cells (TH): release cytokines, regulate other immune cells. Cytotoxic T cells (TC): kill virus-infected and cancer cells. Important for eliminating intracellular pathogens.

3. B cells produce antibodies (immunoglobulins). Functions of antibodies: 1. Label antigens for ingestion by phagocytes (opsonization). 2 . Neutralize viruses and toxins. 3 . Block adhesion of microbes to body tissues. Differences between lymphocytes of adaptive immunity: Each lymphocyte has unique receptors (due to gene rearrangement). Each receptor is specific to one antigenic epitope. This specificity equips the immune system to respond to an enormous variety of antigens. When infection occurs, only the lymphocytes responsive to epitopes found on or in the invading pathogen(s) are activated and proliferate, a rocess known as clonal expansion . Clonal expansion is so named because proliferating lymphocytes give rise to populations of cells with genetically identical receptors that are specific for the same epitope, and these populations therefore represent clones of each other.

4. During infection, lymphocytes must undergo massive clonal expansion to generate enough effector cells . Effector cells (produced during clonal expansion ): T cells → secrete cytokines or act as cytotoxic cells . B cells → produce antibodies. Only a small proportion of lymphocytes become memory cells . Memory cells are long-lived and remain ready to respond to the same microbe . Upon re-infection, they activate rapidly, giving a faster and stronger response than the primary one . Differentiation of lymphocytes (lymphocyte differentiation ): Begins very early in fetal development . Earliest T and B precursors appear in the fetal liver (around 8 weeks of pregnancy ). Later, the bone marrow becomes the major source of new lymphocytes and remains so after birth . asymmetry refers to the ability of a lymphoid progenitor cell to divide into two daughter cells : One retains stem cell-like plasticity . The other starts differentiating into a lymphocyte lineage This mechanism ensures that the body can maintain a pool of stem/progenitor cells while also producing differentiated cells needed for function

5. T-cell differentiation: After being formed in the bone marrow, T-cell precursors travel through the blood to the thymus (a primary lymphoid organ located in the upper chest between the sternum and heart ). The name T cell comes from “ thymus ,” since this is where they mature. The thymus has two distinct regions: outer cortex and inner medulla . Once in the thymus, T-cell precursors are called thymocytes . Thymocytes enter at the cortico-medullary junction (border between cortex and medulla ). From there, they migrate into the cortex, guided by signals from thymic cells, to continue their development.

6. Thymocyte migration: Guided by chemokines and cytokines, thymocytes move slowly from the thymic cortex to the medulla over ~3 weeks. differentiation events during this transit: 1. Rearrangement of T-cell receptor (TCR) genes . 2. Changes in expression of thymocyte cell-surface markers . 3. Selection of thymocytes with functional receptors to continue maturation . 4. Deletion of self-reactive thymocytes to establish self-tolerance . Thymic stromal (supporting) cells —including thymic epithelial cells , macrophages , and dendritic cells (often fibroblasts as well)—are critical for each step by providing signals and costimulation. Major maturation stages are listed as double-negative (DN) → double-positive (DP) → mature T cells; specific markers for each stage are given in the subsequent table/sections of the source

7. Double-Negative (DN) Stage T-cell subsets: T helper (Th) cells are identified by surface marker CD4 . Cytotoxic T (Tc) cells are identified by CD8. Thus, CD4 and CD8 are key cell-surface markers used to distinguish T-cell types. Early thymocytes (just entered the thymus) lack both CD4 and CD8 , because their final fate (Th vs Tc) is not yet decided. → These cells are called double-negative (DN) thymocytes. Location & behavior : DN thymocytes aggregate in the outer cortex of the thymus and actively proliferate under the influence of cytokines, especially interleukin-7 (IL-7).

8. Double Positive ( DP) Stage When a functional TCR β chain is expressed, it allows thymocytes to continue development by rearranging the TCR α chain. The α chain variable region also rearranges through V and J segments, similar to the β chain . Expression of TCR αβ : Once a functional α chain is produced and paired with the β chain, a complete TCR αβ receptor appears on the cell surface . This signals the cell to stop further α-chain rearrangements . CD4 and CD8 expression: At this stage, thymocytes express both CD4 and CD8 , becoming double-positive ( DP ) thymocytes . .

9. Single-Positive Stage : Stromal cells present a wide range of self-antigens . Thymocytes whose TCRs bind strongly to self-antigens are eliminated via apoptosis, preventing autoimmunity . Surviving thymocytes become single-positive (SP), expressing either CD4 (helper) or CD8 (cytotoxic). Mature T Cells : Once they exit the thymus, they are considered mature but naïve, meaning they haven’t yet encountered their specific antigen . They circulate between blood and lymphatics, continuously scanning APCs for their cognate antigen . This search may last years; many naïve T cells never encounter their antigen . Upon recognition, T cells are activated and differentiate : CD4+ helper T cells → proliferate and secrete cytokines to coordinate immunity . CD8+ cytotoxic T cells → proliferate and kill infected or abnormal cells . Activation requires APC stimulation and is shaped by the cytokine environment.

10. Stages In B-Cell Differeiation B cells arise from hematopoietic stem cells in the bone marrow. Unlike T cells (which migrate to the thymus), B cells mature in the bone marrow. Development occurs in two phases: 1. Antigen-independent phase (bone marrow): includes pro-B, pre-B, immature B, and mature B cells . 2. Antigen-dependent phase (after antigen encounter): generates plasma cells (antibody producers) and memory B cells.

11. Immature B cells express a functional IgM BCR, showing gene rearrangement is complete and giving them unique antigen specificity. Because rearrangement is random, some BCRs may recognize self-antigens, which can be dangerous. To prevent this, immature B cells undergo negative selection (central tolerance), where self-reactive cells are eliminated by apoptosis. . Over 90% of immature B cells die in the bone marrow. Those that survive begin to express important surface markers (CD21, CD40, and MHC class II ). . CD21 : helps B cells recognize antigens coated with complement fragments (C3d ). CD40 and MHC class II: essential for interaction with helper T cells (CD4+). A B cell that passes negative selection, expresses IgM, and displays these markers is considered a mature B cell. It then leaves the bone marrow and migrates to the spleen for further development.

12. Mature Bcell In the spleen, immature B cells mature into two main types : 1. Follicular B cells Circulate between blood and secondary lymphoid organs . Localize in lymph node follicles . Require help from CD4+ T follicular helper (Tfh) cells to produce antibodies and memory B cells . Involved in long-term, adaptive immune responses . 2. Marginal-zone B cells Stay in the marginal sinus of the spleen . Respond quickly to blood-borne pathogens, especially polysaccharide antigens from bacteria . Do not require Tfh cell help . Produce large amounts of IgM antibodies . Do not form immunologic memory, so they respond anew with each exposure . General features of mature B cells : All mature B cells express IgM and IgD B cell receptors (BCRs) with the same antigen specificity . Antigen binding to BCR triggers signaling cascades → B cell proliferation . Differentiation outcomes : Plasma cells (antibody-producing ). Memory B cells (only from follicular B cells).

13. Plasma cells are fully differentiated B cells that function as antibody factories. They express low levels of surface immunoglobulin but contain large amounts in their cytoplasm. Morphologically, they have oval nuclei with clumped, dark-staining chromatin, abundant rough ER, and a well-developed Golgi apparatus. In bone marrow and germinal centers, some plasma cells survive long-term in “survival niches” supported by stromal and accessory cells (with cytokines such as IL-6, APRIL, adhesion signals, etc.). Plasma cells outside the bone marrow are usually short-lived, producing antibodies only for a limited time. A key surface marker of plasma cells is CD138.

14. Antigen-presenting cells (APCs) like macrophages and dendritic cells are the first responders to infection. They detect danger signals through innate receptors (e.g., Toll-like receptors), engulf pathogens, and carry their antigens to lymph nodes. In lymph nodes, APCs present antigens to naïve T cells that circulate in search of antigens. Each T cell has a unique T cell receptor (TCR), but only a very small fraction (~1 in 100,000) can recognize a specific antigen. Continuous recirculation of naïve T cells between blood and lymph nodes increases the chance that APCs will find and activate a T cell with the correct TCR. The Role of T Cells in the Adaptive Immune Response

15. Antigen-presenting cells (APCs) present peptide antigens to T cells using MHC (HLA) molecules. Two types of MHC: MHC Class I: Presents intracellular peptides (viruses, intracellular bacteria, tumor proteins) to cytotoxic T cells (CD8⁺), which kill infected or malignant cells. MHC Class II: Presents extracellular peptides (e.g., microbes) to helper T cells (CD4⁺), which coordinate immune responses. T cell activation requires two signals: 1. Antigen recognition – TCR binds the MHC–peptide complex . 2. Costimulation – APC expresses CD80/CD86, which bind to CD28 on T cells. These two signals together transform a naïve T cell into an activated T cell.

16. T Helper (Th) Cells Do not directly kill pathogens but coordinate adaptive immunity . Activated by APCs → secrete cytokines to guide other immune cells . Subsets : Th1: Produce IFN- γ, IL-2, TNF- α → activate cytotoxic T cells & macrophages (fight intracellular pathogens ). Th2: Produce IL-4, IL-5, IL-6, IL-9, IL-10, IL-13 → fight extracellular parasites (worms), contribute to allergies . Th17 : Produce IL-17, IL-22 → recruit granulocytes against extracellular bacteria (can cause tissue damage ). Tfh (T follicular helper): Stay in lymph nodes, help B cells with activation, class switching, affinity maturation, and memory formation . T Regulatory (Treg) Cells CD4⁺CD25⁺ cells (~5% of CD4⁺ T cells ). Suppress immune responses (especially to self-antigens and harmless antigens like food ). Secrete inhibitory cytokines to limit T cell proliferation . Antigen-specific, recognizing peptides via MHC class II . Memory Th Cells Formed after activation . Stay dormant until re-exposed to the same antigen, then respond rapidly with cytokine secretion.

17. CD8⁺ cytotoxic T cells (CTLs): Different from helper T cells; they migrate to infection sites and kill infected cells (with intracellular pathogens and viruses). Unlike NK cells (non-specific), CTLs are antigen-specific because their activity depends on TCR recognition of antigens presented on MHC I . Killing mechanisms : 1. Cytotoxic granules: Release perforin (forms pores in target cell membrane) and granzymes (enter and induce apoptosis by DNA fragmentation and mitochondrial damage ). 2. Death receptor pathway: Bind Fas ligand (FasL) on T cells to Fas receptors on target cells, triggering apoptosis . CTLs therefore induce antigen-specific apoptosis in target cells to eliminate infection. Action of Cytotoxic T Cells

18. Activation of mature B cells: Begins when IgM BCR binds its specific antigen. Follicular B cells require T follicular helper (Tfh) cells → T-dependent antigens. Marginal-zone B cells can respond without Tfh help → T-independent antigens. T-dependent antigens: Usually proteins (because proteins can activate T cells). Follicular B cells bind antigen via BCRs, internalize and process it, then present peptide fragments on MHC class II.

19. Interaction with Tfh cells: Activated B cells migrate to follicle edges to interact with Tfh. Tfh cells provide two signals: 1. CD40L–CD40 binding . 2. Cytokine secretion (e.g., IL-2) → drives B cell proliferation . Fates of proliferating B cells : 1. Differentiate into IgM-secreting plasma cells . 2. Enter germinal centers → undergo: Isotype switching (changing antibody class ). Affinity maturation (improving antibody binding strength ). Memory cell generation (for long-term immunity). Antibody classes: Initially IgM, later IgG (blood), IgA (mucosal/secretions), IgE (allergy). Each class has a specialized role in immune defense.

20. Some B cells, especially marginal-zone B cells, can respond to antigens without T cell help. T-independent antigens are often polymers (e.g., polysaccharides) with repeating elements. These repeating units crosslink multiple BCRs on a single B cell → triggers proliferation and antibody production. Since T cells are not involved, important processes do not occur: Isotype switching Affinity maturation Memory cell formation Immune Response toT-independent antigen