Comprehensive Guide to Hematopoiesis, Lymphoid Organs, and Immune Cell Development

Innate immune cells

First line of defense in the immune response.

Antigen-presenting cells (APCs)

Cells that communicate infection to lymphocytes.

Lymphoid cells

Cells that coordinate adaptive responses and generate memory cells.

Primary lymphoid organs

Sites of immune cell development from immature precursors.

Bone marrow

A primary lymphoid organ where immune cells develop.

Thymus

A primary lymphoid organ where immune cells develop.

Secondary lymphoid organs

Sites where mature lymphocytes first encounter antigen and differentiate into effector and memory cells.

Spleen

A secondary lymphoid organ involved in immune responses.

Lymph nodes

Secondary lymphoid organs where immune responses are coordinated.

Specialized mucosal sites

Secondary lymphoid organs located in the gut and other areas.

Hematopoietic Stem Cells (HSCs)

Cells with the ability to self-renew and differentiate into multiple blood cell types.

Origin and Location of HSCs

HSCs arise in fetal tissues and primarily reside in adult bone marrow.

Rarity of HSCs

Less than 1 HSC per 50,000 bone marrow cells; numbers tightly controlled by division, death, and differentiation.

HSC Function and Regulation

Under homeostatic conditions, most HSCs are quiescent; only a few divide to generate self-renewing daughter cells and progenitor cells.

Proliferation of HSCs during stress

HSCs can proliferate massively during stress or demand, such as infection or chemotherapy.

Example of HSC proliferation

Lethally irradiated mice can be rescued with as few as 10 bone marrow cells from a healthy donor.

HSC Identification

Initial identification relied on negative selection, removing mature lineage markers (Lin⁺ cells).

Modern HSC identification

Uses surface markers and flow cytometry, including CD34, Sca-1, c-Kit.

Monoclonal antibodies in HSC isolation

Facilitate isolation of rare HSC populations.

Long-term HSCs (LT-HSCs)

Most quiescent; retain pluripotency for life and give rise to all blood cells over a lifetime.

Short-term HSCs (ST-HSCs)

Divide more frequently; have limited self-renewal and generate multipotent progenitors (MPPs).

Multipotent progenitors (MPPs)

Have limited self-renewal; highly proliferative and give rise to lymphoid and myeloid lineages.

c-Kit receptor

Binds SCF (stem cell factor), promoting MPP development.

Progressive Loss of Self-Renewal

As HSCs differentiate, self-renewal capacity decreases with each stage from LT-HSC to ST-HSC to MPP.

Lineage Choices of MPPs

MPPs choose between myeloid lineage (CMP) and lymphoid lineage (CLP).

Myeloid Lineage

Gives rise to red blood cells, platelets, and myeloid cells, which are first responders to infection.

Lymphoid Lineage

Gives rise to B lymphocytes, T lymphocytes, innate lymphoid cells (ILCs), and some dendritic cell populations.

MPP

Lymphoid-primed multipotent progenitors that express Flt-3 and lose myeloid potential.

LMPPs

Early Lymphoid Progenitors that downregulate c-Kit and Sca-1 and upregulate RAG1/2 and TdT to initiate lymphocyte receptor formation.

ELPs

Early Lymphoid Progenitors that express IL-7 receptor (IL-7R) and can differentiate into T cells, B cells, or ILCs.

CLPs

Common Lymphoid Progenitors that can differentiate into T cells, B cells, or ILCs.

HSCs

Hematopoietic Stem Cells that maintain many genes in a 'primed' state, making them accessible to transcription machinery.

GATA-2

Transcription factor involved in HSC quiescence and proliferation.

Notch1

Transcription factor that drives T-cell differentiation from CLPs.

Granulocytes

First responders in immune defense, characterized by multilobed nuclei and granules that damage pathogens, regulate immune cell trafficking, and remodel tissues.

Neutrophils

Granulocytes that make up 50-70% of leukocytes, involved in phagocytosis, antimicrobial secretion, and tissue remodeling.

Eosinophils

Granulocytes that account for 1-3% of leukocytes, defending against multicellular parasites and secreting cytokines affecting lymphocytes.

Basophils

Granulocytes that make up less than 1% of leukocytes, responding to parasites and releasing histamine and cytokines.

Mast Cells

Tissue-resident cells that combat parasites and release histamine, maturing in tissues and found in skin and mucosa.

Myeloid Antigen-Presenting Cells (pAPCs)

Include monocytes, macrophages, and dendritic cells, bridging innate and adaptive immunity through antigen presentation.

Flow Cytometry

Modern method that uses monoclonal antibodies to detect surface/internal proteins.

H&E Staining

Visual identification method using hematoxylin and eosin to stain nucleic acids blue and cytoplasmic proteins pink.

Transcription Factor Networks

Complex interactions of transcription factors that regulate lineage decisions influenced by environmental cues.

CMPs

Common Myeloid Progenitors that give rise to the myeloid lineage.

In Vivo Imaging

Technique that allows tracking of immune responses over time and space.

Antigen Presentation Steps

Include secreting proteins to attract/activate other immune cells, internalizing pathogens, and presenting peptides via MHC class II.

Monocytes

Circulate in blood; differentiate into macrophages or tissue-specific cells; patrol blood vessels; inflammatory monocytes enter infection sites.

Macrophages

Phagocytosis of pathogens/damaged cells; act as pAPCs; tissue-resident macrophages originate embryonically (Kupffer cells, microglia, alveolar macrophages).

Dendritic Cells (DCs)

Capture antigen in periphery; present to naïve T cells in lymph nodes; arise from myeloid and lymphoid progenitors; initiate adaptive immunity.

Follicular Dendritic Cells (FDCs)

Not from HSCs; located in B-cell follicles; regulate B-cell activation, not T-cell activation.

Opsonization

Antibodies bind pathogens → enhance phagocytosis by macrophages (~4000-fold increase in rate).

Erythrocytes (RBCs)

Carry oxygen, anuclear in mammals.

Erythrocyte Functions

Can bind antibody complexes and generate antimicrobial compounds (e.g., nitric oxide).

Erythrocyte Precursors

Erythroblasts (nucleated; lose nucleus before maturation).

Megakaryocytes

Large bone marrow cells that produce platelets.

Platelet Functions

Contribute to blood clotting, barrier formation at epithelial surfaces, and some immune functions.

Professional APCs

Monocytes/macrophages/dendritic cells activate T lymphocytes; tissue-resident macrophages originate embryonically.

Lymphocytes

Central to adaptive immunity and the formation of immune memory; account for 20-40% of circulating white blood cells.

B lymphocytes (B cells)

A major lymphoid population involved in adaptive immunity.

T lymphocytes (T cells)

A major lymphoid population involved in adaptive immunity.

Innate lymphoid cells (ILCs)

Include natural killer (NK) cells; a major lymphoid population.

Lymphocyte Features

Small, round cells with large nuclei; visually indistinguishable between T and B cells.

CD Proteins

Cluster of Differentiation, standardized nomenclature for surface proteins; expression patterns vary with developmental stage and activation state.

Unique Antigen-Specific Receptor

Each lymphocyte expresses a unique receptor: BCR on B cells and TCR on T cells.

Clonal Expansion

All progeny of a lymphocyte share the same receptor specificity.

Naïve Lymphocytes

Encounter antigen and differentiate into effector and memory cells.

B-cell Receptor (BCR)

A membrane-bound antibody that distinguishes B lymphocytes.

B Lymphocyte Functions

Bind specific antigen, undergo somatic hypermutation to improve antigen binding, and class switching to produce different antibody classes.

Plasma Cells

Specialized for antibody secretion; may live weeks to years.

T-cell Receptor (TCR)

Recognizes antigen peptides on MHC molecules.

MHC Class I

Expressed by nearly all nucleated cells; recognized by CD8 cytotoxic T cells.

MHC Class II

Expressed by pAPCs; recognized by CD4 helper T cells.

CD4 T Helper (Th) Cells

Subsets include Th1 & Th17 for intracellular pathogens, Th2 & Tfh for extracellular pathogens, and regulatory T cells (Treg) which suppress immune responses.

CD8 Cytotoxic T Cells (CTLs)

Kill virus-infected or abnormal cells.

Somatic hypermutation

A process that improves antigen binding by B cells.

Class switching

The process by which B cells produce different classes of antibodies.

Professional antigen-presenting cells (pAPCs)

B cells that present antigens to T cells via MHC class II and receive T-cell help to differentiate.

Regulatory T cells (Treg)

Subgroup of CD4 T cells that suppress immune responses.

NKT cells

Cells that share features of both T cells and innate immune cells, recognizing lipid antigens via CD1 molecules.

Natural killer (NK) cells

Cytotoxic cells that target virus-infected or tumor cells, constituting 5-10% of peripheral lymphocytes.

Missing-self recognition

A mechanism by which NK cells identify and kill cells lacking MHC I.

Antibody-dependent cell cytotoxicity (ADCC)

A process by which NK cells kill target cells via Fc receptors.

Key concepts of lymphocytes

Lymphocytes include B cells, T cells, and ILCs, distinguished by CD proteins, and are highly diverse and adaptable to pathogen challenges.

Quiescence

A non-dividing state of HSCs.

Proliferation

The process by which HSCs divide to form progenitors.

Differentiation

The process by which HSCs develop into specific cell types.

Trafficking

The movement of HSCs within tissues.

Yolk Sac

The early site of blood cell formation providing primitive nucleated erythroid cells for oxygen delivery.

Aorta-Gonad-Mesonephros (AGM) region

The site where early definitive HSCs appear during embryonic development.

Placenta

The site where the HSC pool expands rapidly, surpassing AGM/yolk sac numbers.

Fetal Liver

The main site of hematopoiesis by late gestation, dominated by early erythroid progenitors.

Bone Marrow in Childhood

Hematopoietic activity shifts from most bones to selected bones (vertebrae, ribs, sternum, skull, pelvis, parts of humerus/femur) by age 18.

Endosteal niche

The niche lining the bone surface where HSCs reside.

Perivascular niche

The niche lining blood vessels, primarily housing long-term, quiescent HSCs.

Stromal cells

Cells in niches that regulate HSC behavior, including endothelial cells, perivascular cells, sympathetic nerves, macrophages, and osteoblasts.

B lymphocytes

Cells that complete most maturation in the bone marrow and exit via central sinuses for final maturation in the spleen.

T lymphocytes

Cells that leave the bone marrow at an immature stage and complete maturation in the thymus.

Aging Effects on Bone Marrow

With age, fat replaces ~50% of marrow, reducing hematopoietic efficiency.

Thymocytes

Immature T cells in the thymus that generate unique T-cell receptors (TCRs).

Negative selection

The process where thymocytes with too-high affinity for self-peptide/MHC die to prevent autoimmunity.