T Cell Maturation Stages

T Cell Maturation Stages

• T cell maturation depends on thymic education and departure from the thymus.
• The T cell lineage differentiates into three maturation stages:
  • Alpha-beta T cell receptor (TCR) expressing cells
  • Gamma-delta TCR expressing cells
  • NK cell surface marker maintaining cells
• Hematopoietic stem cells differentiate into CLP cells and migrate to the thymus.
• In the thymus, precursor cells acquire surface markers that differentiate the stages.
• Pro T cells are double negative, lacking TCR, CD3, CD4, and CD8 markers.
• Pre T cells encountering peptides with MHC Class I or II differentiate into CD8 cytotoxic T cells or CD4 helper T cells, respectively.
• Alpha-beta lineage T cells that pass selection migrate to the periphery.
• T cells bypassing selection differentiate into the gamma-delta lineage.
• Gamma-delta T cells migrate to respiratory organs, skin, and peritoneal cavity early in embryogenesis.
• T cells failing selection or binding to self-peptides are eliminated.
• Only 1-5% of thymocytes graduate as T cells.
• Alpha-beta T cells express TCR, CD3, and either CD4 or CD8, plus adhesion molecules.
• Gamma-delta T cells go through less stringent selection, unlike alpha-beta T cells.

T Cell Developmental Surface Markers

• Hematopoietic stem cells (HSC), CLP, or prothymocytes lack mature surface markers before entering the thymus.
• Thymocytes can develop gamma-delta TCR and CD3 receptors and exit the thymus early in development.
• Remaining thymocytes undergo further selection to develop alpha-beta TCR, CD3, CD4 and CD8 receptors
• Single-positive thymocytes recognize peptides presented on MHC Class I or II molecules.
• T cells differentiate into mature T cells with CD4 or CD8 markers.
• NK T cells bind to CD1d instead of MHC and have diverse surface receptors.

B Cell Maturation Stages

• Occurs in the bone marrow with immunoglobulin-producing cells appearing as early as three weeks of fetal development.
• Bone marrow-derived lymphocytes (B cells) generate and display immunoglobulins on their surface with B cell receptors (BCRs).
• B cells remain in the bone marrow, unlike T cells that differentiate in the thymus.
• B cells use a complex genetic rearrangement system.
• B cells arise from CLPs and differentiate into the B cell lineage.
• Early B cells, or pre-pro B cells, express Ig-alpha and Ig-beta genes required for the mature BCR molecule.
• Pro B cells bind to stromal cells activating an IL-17 signal modulated by C kit.
• IL-17 stimulates B cells to differentiate into pre B cells that express rearranged Ig light chains.
• Immature and mature B cells express heavy chains plus kappa or lambda genes.
• Mature B cells express cell surface IgM and IgD.
• B cell development consists of three stages:
  • Generation of mature, immunocompetent B cells
  • Activation of B cells
  • Differentiation of B cells into plasma cells
• The markers distinguishing B cell lineage is antigen-independent.
• Pro-B cells express a surrogate light chain (SLC).
• Early pre-B cells express pseudo IgM plus SLC.
• Late pre-B cells express fully formed immunoglobulin light chains.

B Cell Subsets

• Immature B cells express heavy and light immunoglobulin genes on their surface.
• Mature B cells co-express IgM and IgD.
• Two B cell subsets emerge:
  • B-1b cells develop during fetal life, making up 5% of the total population, expressing surface IgM with little or no IgD.
  • B-2b cells are the dominant subtype, expressing surface IgM and IgD.
• B-1b cells may contribute to innate immunity, like gamma-delta T cells.

Thymic Involution

• Aging of the thymus (thymic involution) leads to a reduction in the production of new T cells.
• Thymic involution results in a less adaptive and less diverse immune response with age.
• Thymic involution can increase older individuals' susceptibility to infections, reduce vaccine responsiveness, and promote immune-related conditions.

Clonal Expansion

• Proliferation of large pre-B cells results in production of many B cells with the same V_H chain.
• Each pre-B cell randomly rearranges its light chain genes, resulting in different antigen specificities due to different V_L regions.

B Cell Maturation

• Pre-Pro B Cells: Early B cells that express Ig-alpha and Ig-beta genes necessary for the BCR.
• Pro-B Cells: Bind to stromal cells activating IL-17 signaling modulated by C-kit, promoting differentiation.
• Pre-B Cells: Express rearranged Ig light chains, with complete heavy chain rearrangement and light chain rearrangement begins.
• Immature B Cells: Express IgM on their surface with rearranged heavy and light (kappa or lambda) chains.
• At the "immature" stage, B cells have undergone gene rearrangement but is not yet fully functional.
• Mature B Cells: Co-express IgM and IgD and exit the bone marrow to secondary lymphoid organs.

c-Kit

• c-Kit, also known as CD117, is a receptor tyrosine kinase.
• c-Kit plays a role in the development and survival of hematopoietic stem cells and progenitor cells.
• c-Kit is expressed on pro-B cells, and its activation is necessary for pro-B cell differentiation.
• c-Kit binds stem cell factor (SCF), produced by stromal cells in the bone marrow.
• c-Kit signaling promotes pro-B cell survival by protecting against apoptosis (programmed cell death).
• c-Kit signaling helps guide the pro-B cells toward further differentiation into pre-B cells.
• c-Kit is also involved with proliferation of the B cells.

Surrogate Light Chain (SLC)

• The SLC plays a role in early B cell development during the pre-B cell stage, where it forms the pre-B cell receptor (pre-BCR).
• The SLC ensures B cells develop functional B cell receptors (BCRs) before differentiating further.
• The surrogate light chain (SLC) is made up of two proteins: VpreB and λ5, which mimic the light chain.
• The pre-BCR allows the B cell to determine whether the newly rearranged heavy chain is functional.
• SLC is expressed during the early pre-B cell stage before expression of a real light chain (kappa or lambda).
• If signaling is correct, it sends survival signals allowing it to continue transforming into an immature B cell.
• If signaling is incorrect the pre-B cell goes through apoptosis.
• After successful testing of the heavy chain, it will rearrange light chain genes.
• The surrogate light chain serves as a placeholder in the early stages.
• VpreB is structurally similar to the variable region of the light chain.
• λ5 is structurally similar to the constant region of the light chain.

T cell maturation depends on thymic education where T cell lineage differentiates into alpha-beta TCR expressing cells and gamma-delta TCR expressing cells. Pro T cells are double negative, lacking TCR, CD3, CD4, and CD8 markers. Alpha-beta lineage T cells that pass selection migrate to the periphery.