T and B lymphocyte development

• Recognition of foreign antigen


  • the elimination of foreign agents by the adaptive immune system (IS) resides in the functional activity of T and B cells.
  • The ability to recognise foreign antigens reside in the TCR in T cells and BCR (Ig) in B cells
  • each T and B cell produced express a unique antigenic receptor. Therefore the adaptive IS has the ability to interact with any pathogen.
  • The production of diversity of T and B cells occurs during their development
• light chain of antibody is made up of-


  Variable gene, joining gene and constant gene
• heavy chain of antibody is made up of-


  variable gene, D gene, joining gene and constant gene.
• each T cell receptor is made up from different gene segments - alpha chain


  • variable gene, joining gene and constant gene
• eachTCR is made up from different gene segments- beta chain 


  • variable gene, D gene, joining gene, constant gene.
• generation of diversity 


  generate diversity by using different combinations of the V and J gene segments
• gene segments in light (K) chain 


  • 40 Variable genes
  • 5 joining genes
  • recombinatorial diversity = 200
• generation of diversity of variable domain of TCR a chain


  • 70V and 61J
  • recombinant oral diversity = 4270
• the number of gene segments encoding human immunoglobulin variable domain

  • V segment - VLk= 40, VLy -30, VH-57
  • D segment - VLk- 0, VLy-0, VH - 27
  • J segment - VLk- 5, VLy- 4, VH-6
  • recombinatorial diversity - H chain - 8262, k chain-200, L chain - 120
  • combinatorial diversity- HxK chain- 1.7x10^6 + HxI - 1x10^6
  • total - 2.7x10^6
• number of gene segments encoding the human T cell receptors variable domain

  • V segment - TCR Va- 70, TCR Vb- 52
  • D segment TCR Va- 0, TCR Vb-2
  • J segment - TCR Va- 61, TCR Vb- 13
  • recombinatorial diversity- 4270- TCR a chain, TCR b chain - 1352
  • combinatorial diversity - TCR a b 4270 x 1352 = 5.7x10^6
• somatic mutation


  • mechanisms for introducing mutations into V regions of activated B cells (antigen driven) - increases antibody affinity
  • occurs in germinal centres
  • Only occurs in B cells
• class switching 


  • main purpose is that each class displays a different biological function
  • only occur in B cell
• T cell receptor diversity

  • same as immunoglobulin ( BCR)
  • BUT
  • No somatic mutation
  • No class switching
  • Diversity even more focused on CDR3
  • More N region diversification
• what does a stem cell need to become a lymphocyte 


  • to become a T cell need to express a receptor - important for stem cell to undergo gene rearrangement
  • to become a B cell - need to express an antigen receptor, important stem cell undergo gene rearrangement
• stem cell to T cell processes 


  • B chain genes - germline - undergo VDJ rearrangement
  • A chain genes- germline- undergo VJ rearrangement
  • surface T cell receptor - absent - TCR+ CD3+CD4/CD8
• stem cell to become B cell


  • H chain genes- germline - VDJ rearranged
  • L chain genes- germline- VJ rearranged
  • surface Ig- absent- IgD ad IgM made from alternatively spliced H chain transcripts
• B- lineage cell development

  
• what does disruption of gene rearrangement lead to?


  • absence of T and B cells
  • eg- equine SCID- severe combined immunological deficiency.
• what does receptor gene disruption lead to 


  • absence of T and B cells
  • Mainly T
• what facilitates the development of B cells


  • microenvironement - stromal cells by providing the appropriate factors (soluble) and cell- cell interactions.
• stem cell to B cell development 


  • stem cell adhesion to bone marrow stromal cell.
  • induction of gene rearrangement leads to early pro B cell.
  • survival and proliferation
  • late pro B cell produced -
  • pre B cell produced
  • Immature B cell produced
• T cells developed where?


  • in the thymus
  • stem cells enter and undergo
  • lineage commitment
  • repertoire selection - education - which T cell they become
  • functional maturation
  • T cells developed
• T cell maturation in thymus

  
• function of thymus 


  • primary site for T cell development - upon entry into thymus, stem cells receive the necessary signals to become functional T cells
  • these instructions are provided by the thymic microenvironment in particular the thymic epithelial cells- this involved cell-cell contact and the production of soluble factors
  • thymus is critical for the development of mature and competent T cells
  • without a thymus the host lack peripheral T cells leading to host being immunocompromised.
• development of adaptive immunity

  • newborn reliant on passive immunity from mother
  • adaptive immunity still developing in newborn
  • innate immunity is essential for protection
• what is passive immunity

  • immunity passively transferred by
  • lactation - secreted in breast milk
  • crossing placenta
  • maternal IgG decreases after birth as newly synthesised IgM and IgG develops
• immature thymocytes are located in the


  • cortex
• How are lymphocytes developed


  • generated from stem cells and their development into which lymphocyte is governed by their microenvironment. -thymus and bone marrow which induces/ promotes the differentiation and maturation of lymphocytes
• How is diversity achieved 


  • through random combination of gene segments, imprecise joining, nucleotide addition/ removal - antigen independent somatic hypermutation - only in B cells- antigen dependent
• why do T cells not mutate 


  • as they rely on recognising the broken down peptide presented by MHC, mutations could lead to to them not recognising the peptide