The development of T cells in the thymus

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1 T cells rearrange their receptors in the thymus whereas B cells do so in the bone marrow. The development of T cells in the thymus The lobular/cellular organization of the thymus Immature cells are called thymocytes The thymus is a primary lymphoid organ (lymphocytes develop and mature to the stage they can respond to infection) Epithelial cells of the thymus form a network surrounding developing thymphocytes (thymic stroma) 1

2 The importance of the thymus DiGeorge s syndrome (thymus fails to develop) clinical symptoms: wide range of opportunic infections Thymectomy (removal of thymus) reduced production of new T cells is not affected later in life (T cells are long lived) The development of T cells in the thymus T cells develop in the thymus (progenitor cells that enter the thymus are not committed to the T-cell lineage Thymocytes do not express CD4 or CD8 (and are called DN (Double Negative) Thymocytes commit to the T-cell lineage before rearranging their T-cell receptor genes Commitment to the T cell lineage involves changes in gene expression and in cell surface markers T-cell development is driven by the receptor Notch 1 T cell marker IL-7 produced by stromal cells is critical B cell equivalent is Pax-5 2

3 Two lineages of T cells arise from a common thymocyte progenitor T cells that fail to make reproductive arrangements die by apoptosis and are ingested by macrophages in the thymic cortex γδ needs two succesful rearrangements 80% succes rate for beta chain rearrangement apoptotic cells are scattered through the cortex but rare in the medulla apoptotic cells are stained red and macrophages blue DP=Double Positive Gene rearrangement in double-negative thymocytes leads to assembly of either a γ:δ receptor or a pre-t-cell receptor Thymocytes can make 4 attempts to rearrange a Tcrβ-chain gene (80% succes rate) first rearrangement joins D to J and second joins V to DJ Maximal two attempts per maternal or paternal inhereted chromosome 3

4 Comparison of the Pre-T-cell receptor and T-cell receptor Rearrangement of the α-chain gene occurs only in pre-t cells after formation of pre-t cell receptor, RAG are temporarily inactivated and pre-t cell is induced to proliferate which creates clonal expansion of cells allexpressing the same chain only V and J segments, thus only one succesful rearrangement is needed multiplicity of V and J elements allows successive rearrangeents Thymal development of double positive T cells in a nut shell 4

5 T cells that recognize self-mhc molecules are positively selected in the thymus Receptor editting to match MHC only 2% of DP thymocytes passes positive selection If first gene rearrangement of Tcr α-chain is productive, subsequent positive selection (MHC) will shut of RAG gene transcription. Continuing α-chain gene rearrangement increases the chance for positive selection no allelic exclusion at the α-chain locus, a small proportion of T cells (1 to 2%) has two receptors, of which only one is functional. Positive selection determines expression of either the CD4 or the CD8 co-receptor T cells specific for self antigens are removed in the thymus by negative selection No MHC class I or II expression is called Bare Lymphocyte syndrome MΦ and DC responsible for negative selection are derived from the bone marrow 5

6 Positive and negative selection of the T-cell repertoire Tissue-specific proteins are expressed in the thymus and participate in negative selection (AIRE=autoimmune regulator) Aire defficient patients suffer from autoimmune polyglandular syndrome type I which is a broad spectrum autoimmune diease Negative selection by thymus produces central tolerance Positive and negative selection of the T-cell repertoire Regulatory CD4 T cells (T reg ) comprise a distinct lineage of selfreactive T cells. -express CD25 (cell surface) and FoxP3 encoded on the x chromosome (transcriptonal repressor protein) - FoxP3 deficiency results in polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) It takes two to Tango Positive and negative selection of the T-cell repertoire T cells undergo further differentiation in secondary lymphoid tissues after encounter with antigen The T cell rich areas of secondary lymphoid tssues provide specialized sites where naive T cells are activated by their specific antigens. 6

7 Positive and negative selection of the T-cell repertoire T cells undergo further differentiation in secondary lymphoid tissues after encounter with antigen T cell developments in the Thymus in a series of stages Most T-cell tumors represent early or late stages of T-cell development Activation of naive T cells on encounter with antigen Immature dendritic cells capture antigen and migrate to secondary lymphoid tissue (T cell regions of the cortex) where they become mature/ activated dendritic cells T cell activation (priming) may result in various T cell effector functions Macrophages (role in defense and repair of damaged tissue) are resident in tissues 7

8 Dendritic cells carry antigens from sites of infection to secondary lymphoid tissues Dendritic cells use various pathways to process and present protein antigens Antigen capture by dendritic cells takes place by a) receptor mediated endocytosis b) macropinocytosis (ingestion of large amounts of extracellular fluid) Activation of naive T cells on encounter with antigen Naive T cells first encounter antigen presented by dendritic cells in secondary lymphoid tissues dendritic cells enter via afferent lymp (drains from the site of infection Naive T cells enter the lymph node by a) squeezing through blood capillaries (high endothelial venules) and enter the cortecal region b) through the lymph from an upstream lymp node (efferent lymp) How the lymph network works In any given infection only 1 in 10 4 to 1 in 10 6 of the total pool of circulating T cells is activated. 8

9 5/11/11 Homing of naive T cells to secondary lymphoid tissues is determined by chemokines and cell-adhesion molecules Naive T and B cells circulate in the blood and enter lymph nodes by crossing high endothelial venules CCL19/21 secreted by stromal cells. Naive B and T cells express CCR7. Cells are guided by a chemokine gradient More about lymphocyte adhesion to professional antigen-presenting cells (APC) Transient adhesive interactions between T cells and DC are stablized by specific Ag-recognition DC secrete CCL18 which attracts naive T cells DC-SIGN a lectin unique to activated DC 9

10 Activation of naive T cells requires a co-stimulatory signal delivered by a professional antigen-presenting cell CTLA4 is expressed only on activated T cells, is similar to CD28 but binds much stronger to its ligand B7 and works as an atagonist signal 1 induces clonal expansion but only when signal 2 is delivered B7.1 and 7.2 are known as costimulatory molecules In the absence of infection, DC, MQ and B cells do not express co-stimulatory molecules (signal 2). Thus the capacity of professional APC to activate naive T cells is a direct consequence of infection, being induced by signalling by Toll-like receptors or other receptors from the innate immune system Activation of naive T cells on encounter with antigen Secondary lymphoid tissues contain three kinds of professional antigen-presenting cells which populate distinct areas There is a concentraton gradient of (sphingosine 1-phosfate (S1P) from the lymp/blood to the secondary lymphoid tissues T cells activated by Ag suppress the expression of S1P receptors for several days (makes them stay in the lymph node while they differentiate into effector cells). Later they are drawn away by the gradient of S1P 10

11 The immunological synaps (T cell synaps) A simple outline of the intracellular signalling pathway initiated by the T cell receptor, CD4 and CD28 ITAM = immune receptor tyrosine-based motif IL2 production Activated T cells secrete and respond to IL-2 (part I) Activated T cells secrete and respond to IL-2 (part II) IL-2 drives clonal expansion Cyclosporine-A, Tacrolimus (FK506), and Rapamycine are immunosuppressive drugs that inhibit IL-2 production or signalling from the IL-2 receptor 11

12 Ag recognition by a naive T cell in the absence of co-stimulation leads to anergy On activation, CD4 T cells acquire distinctive helper functions Anecdote: Failure of CD28 clinical trial Different cytokine profiles drive the differentiation of CD4 positive T cells that produce different cytokines and possess distinct functions Polarization of immune responses in different clinical forms of leprosy cell mediated immunity (T H 1) T H 1 T H 2 humoral immunity (T H 2) 12

13 Naive CD8 T cells are activated to become cytotoxic effector cells in several different ways Effector T-cell responses to infection do not depend on co-stimulatory signals Integrin VLA-4 enables effector T cells to home to inflamed tissue The three types of effector T cell produce distinct sets of effector molecules 13

14 LG lytic granules MTOC microtubule organizing center Kiss of death Cytotoxic CD8 T cells are selective and serial killers of target cells at sites of infection Cytotoxic T cells kill their target cells by inducing apoptosis or programmed cell death T H 1 CD4 cells activate macrophages to become highly microbicidal Two pathways; 1 by granzymes, perforin and granulysin 2 Fas ligand conjugate pair, activation requires two signals 14

15 T H 1 cells coordinate the host response to pathogens that live in macrophages Granuloma s form when an intracellular pathogen or its constituents resist elimination (MT) The properties and functions of effector T cells CD4 T H 2 cells activate only those B cells that recognize the same antigen as they do CD4 T H 2 cells activate only those B cells that recognize the same antigen as they do Regulatory CD4 T cells (Tregs) limit the activities of effector CD4 and CD8 T cells 15

16 molecular components recognized both by B and T cells make effective vaccines The adaptive T cell response has two distinct stages 16