8_b_t_cell_development.md

Development of B Lymphocytes

Lymphocytes

HSC

There is a (somewhat continuous) lineage of differentiation.

HSC -> MPP -> CLP -> pro B-cell

MPP - Multi Potent Progenitor, (myeloid + lymphoid only) CLP - Common Lymphoid Progenitor, committed to NK / T / B

Bone marrow stromal cells secrete key cytokines and present ligands necessary to differentiate HSCs into B cells (FLT3). The stromal cells actually remain in contact with developing B cells for much of the lifecycle.

Lymphocytes derive from HSC in the bone marrow

B-cell development begins with heavy chanin rearrangement

pre-B-cell receptor tests for production of a complete heavy chain

signals transition from pro B-cell to pre B-cell

pre-B-cell receptor signaling further inhibits heavy chain recombination

is responsible for allelic exclusion

Pre B-cells rearrange the light chain and express surface immunoglobulin

Immature B-cells are tested for autoreactivity before they leave the bone marrow

Lymphocytes that encounter self antigens in the periphery are eliminated / inactivated

Immature B-cells arriving in the spleen often die and require positive signals for maturation / long term survival

Become follicular B-cells + marginal B-cells

Development of T Lymphocytes

T-cell progenitors originate in bone marrow but all important development events occur in the thymus

Commitment to the T-cell lineage occurs in the thymus following Notch signaling

Major transcription factors from Notch signaling:

TCF1 / GATA3 -> CD3 + Rag3

T-cell precursors proliferate extensively in the thymus but most die there

Successive stages in thymocyte development are marked by changes in surface molecules

Thymocytes at distinct developmental stages are found in different parts of the thymus

Alpha/beta and gamma/delta T cells arise from a common progenitor

Successful synthesis of beta chain allows the production of a pre-TCR that triggers cell proliferation + blocks further beta chain rearrangement

T-cells undergo successive alpha chain rearrangement until positive selection or cell death

Positive and Negative Selection of T cells

Prior to alpha/beta receptor expression, development is independent of peptide:MHC interaction.

Only thymocytes whose receptors interact with self peptide:MHC complexes survive

Positive selection coordinates expression of CD4 or CD8 with the specificity of the receptor

Thymic cortical epithelial cells mediate positive selection of developing thymocytes

T cells that react strongly with self antigens are deleted in the thymus

The strength of the signals for positive and negative selection must differ