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THE DEVELOPMENT OF T LYMPHOCYTES DEVELOPMENT OF T LYMPHOCYTES * Development of T and B cells have similarities and differences * Similarities * Derivation from stem cells in BM * Antigen receptors produce by gene rearrangements * Differences * B cells rearrange receptor genes in BM while T cells rearrange receptor genes in thymus * T cell receptors have MHC restriction DEVELOPMENT OF T LYMPHOCYTES * T cells originate from stem cells in bone marrow and migrate to thymus to mature * Thymus * * * * * Lymphoid organ in upper anterior thorax Primary lymphoid organ Fully developed before birth Increases in size until puberty then degenerates Degeneration has no discernible impact on T cell immunity CELLULAR ORGANIZATION OF THE THYMUS * Consists of two symmetrical lobes each enclosed by capsule from which trabeculae extend and divides each lobe into lobules * Lobule consists of * Cortex * Immature thymocytes, cortical epithelial cells and macrophages * Medulla * Mature thymocytes, medullary epithelial cells, dendritic cells and macrophages DEVELOPMENT OF T CELLS IN THYMUS * Immature cells enter thymus at subcapsular region of outer cortex * Express neither CD4 nor CD8 * Called “double-negative” thymocytes * Double negative thymocytes initially express * CD44 and CD25 * CD44 expression declines * Rearrangement of genes for beta, gamma and delta chains DEVELOPMENT OF T CELLS IN THYMUS * Lineages of T cell receptors * Alpha:beta * Gamma:delta * “Thymocytes, start your rearrangements” * Productive rearrangement of gamma and delta genes * Gamma:delta receptor * Productive rearrangement of beta gene * Rearranged beta chain assembled with surrogate alpha chain (pTalpha) to form “pre T cell receptor” * Alpha:beta receptor GENE REARRANGEMENT IN ALPHA:BETA T CELLS * Beta chain rearranges first with potential 80% success rate * Locus on homologous chromosome * Two sets (beta 1 and 2) of D, J and C gene segments * Beta chain combines with * Surrogate alpha chain (pT-alpha), CD3 and zeta * Pre T cell receptor * Beta chain rearrangement stops and CD4 and CD8 expressed * “Double-positive” thymocytes * Alpha chain rearranged and pairs with beta chain POSITIVE AND NEGATIVE SELECTION OF DOUBLE POSITIVE T-LYMPHOCYTES * Alpha:beta T cells are screened * Positive selection * Selection of immature T cells which recognize self MHC molecules * Negative selection * Elimination of immature T cells which are activated by self peptides * Gamma:delta T cells are not screened POSITIVE SELECTION OF ALPHA:BETA T CELLS * Takes place in cortex of thymus * Mediated by self peptide:self MHC molecules presented on surface of cortical epithelial cells * Cortical epithelial cells express * MHC class I and MHC class II molecules * T cells which recognize self peptide:self MHC continue maturation * T cells which do not recognize self peptide:self MHC commit apoptosis POSITIVE SELECTION CONTROLS EXPRESSION OF CD4 AND CD8 CO-RECEPTORS * “Double-positive” thymocyte interacts through its alpha:beta receptor with either * MHC I or MHC II * Interaction results in “single-postive” thymocyte * Interaction with MHC I results in CD8 T cells * Interaction with MHC II results in CD4 T cells * Mechanism by which interaction selects for “singlepositive” thymocytes is unknown BARE LYMPHOCYTE SYNDROMES * Immunodeficiency showing importance of MHC molecules in selection of co-receptors and T cell development * Disease characterized by * Severe immunodeficiency * Lack of expression of either MHC I or MHC II by lymphocytes and thymic epithelial cells * Persons who lack expression of MHC I * CD8 (-) and CD4 (+) * Persons who lack expression of MHC II * CD8 (+) and CD4 (-) REMOVAL OF T CELLS SPECIFIC FOR SELF ANTIGENS IN THYMUS BY NEGATIVE SELECTION * T cells which strongly bind self peptide:self MHC molecules are potentially autoreactive * Negative selection mediated by * Dendritic cells and macrophages at cortico-medullary junction of thymus * Autoreactive T cells undergo apoptosis * Mechanisms of positive and negative selection unknown * Positive and negative selection results in highly personalized T cell immunity DEVELOPMENT OF T CELLS AFTER LEAVING THYMUS * Small percentage of alpha:beta T cells survive positive and negative selection * Mature naïve T cells recirculate between blood and secondary lymphoid tissues * Mature T cells are longer liver than mature B cells * Encounter with antigen * T cell rich areas of secondary lymphoid tissues DEVELOLPMENT OF T CELLS AFTER LEAVING THYMUS * Following activation by antigen T cells differentiate into different effector cells * CD8 to cytotoxic T cells * CD4 to * TH1 * TH2 * Healthy individuals * Twice number of CD4 as CD8 cells * Flow cytometry * Identification and enumeration of T cells REFERENCE RANGES FOR T LYMPHOCYTES IN ADULTS Absolute # Percent CD3 782-2204 60-87 CD4 443-1345 31-58 CD8 171-914 13-40 CD4/CD8 ratio > 1.0 T LYMPHOCYTES AND MALIGNANT DISEASES * T cell cancers primarily associated with * Early and late stages of development * Classification of malignant T-cells diseases * Leukemia * Malignant disease with origin in bone marrow * Chronic lymphocytic leukemia (CLL) * Lymphoma * Malignant disease with origin in lymph nodes or lymphatic tissue * Mycosis fungoides and Sezary syndrome Figure 5-16 ACUTE LYMPHOBLASTIC (LYMPHOCYTIC) LEUKEMIA (ALL) * Approximately 4,000 new cases each year in US * Most common cancer of children * Majority resemble immature B cells * B-ALL or C (common)-ALL * Minority resemble immature T cells * T-ALL ACUTE LYMPHOBLASTIC (LYMPHOCYTIC) LEUKEMIA (ALL) * Causes * Translocation of genes * Philadelphia translocation involving 9 and 22 (20%) * Acquired mutational event * Effects * Turns on oncogene * Turns off tumor suppressor gene * Results * Large numbers of immature, abnormal lymphocytes produced in bone marrow * Decrease production of RBC, WBC and platelets with resulting clinical manifestations ADULT T-CELL LEUKEMIA / LYMPHOMA (ATLL) * Cutaneous T-cell lymphoma (CTCL) * CD4 origin * Incubation period * 20 to 40 years * Clinical courses * Acute (aggressive) * Chronic (indolent) * Etiology * Human T-Cell Lymphotrophic Virus I (HTLV-I) ADULT T-CELL LEUKEMIA / LYMPHOMA (ATLL) * Human T-cell Lymphotrophic virus type 1 (HTLV-1) * First human retrovirus identified * Endemic in southern Japan, Caribbean and central Africa * Uses CD25 to enter lymphocytes * Virus is immunosuppressive and oncogenic * Mechanism of immunosuppression * Stimulation of CD4 TH1 cells * Mechanism of oncogenicity * Not well illucidated * Tax protein central molecule MYCOSIS FUNGOIDES (MF) * Cutaneous T-cell lymphoma (CTCL) * Most common (50%) * CD4 T cells * Etiology is unknown * Clinical course * Indolent * Cutaneous patches to plaques to tumors (mushroomlike) w/wo pruritis MYCOSIS FUNGOIDES (MF) * Laboratory diagnosis * Histopathology of skin biopsy * Hematoxylin and eosin stain * Immunohistochemical stains * Treatment depends on stage * Topical steroids and nitrogen mustards * PUVA photochemotherapy * Psoralens * UVA radiation SEZARY SYNDROME (SS) * Cutaneous T-cell lymphoma (CTCL) * CD4 origin * Considered terminal stage of MF * Clinical manifestations and course * Skin is bright red, scaly and very itchy * Entire skin involved, lymph nodes, viscera and blood * Aggressive course * Death by OI secondary to immunosuppression SEZARY SYNDROME (SS) * Clinical pathology * Sezary cells (> 1,000/uL) in peripheral blood * CD4/CD8 ratio of > 10 * Loss of normal T cell antigens * CD2, CD5, CD7 * Anatomic pathology * Skin biopsy shows * Cerebriform lymphocytes in epidermis and upper dermis with Pautrier’s microabscess formation CASE STUDY * 49 year WM presents with 3 month history of * Lesions located on buttocks and hips * Flat, pinkish-red patchy lesions * Sometimes itchy * Differential diagnosis of * Eczema, psoriasis, contact dermatitis * Treatment * Topical and oral steroids CASE STUDY * Cutaneous rash and itch intermittent for 5 years * Presents at age 54 with more extensive rash and itch * Flat, pinkish-red patchy lesions (25%) * Dry, slightly raised scaling plaques which are very itchy (75%) * Specimens * Punch biopsy of skin for histopathology * Blood for CBC with diff and flow cytometry CASE STUDY * Histopathology * Hematoxylin / Eosin stain * Dense infiltrate of medium sized cerebriform lymphocytes in epidermis, upper dermis and perivascular. Pautrier’s microabscesses present. * Immunohistochemical stains * Strong reactivity with CD3 and CD4 T cell antigens * CBC showed < 1,000 Sezary cells/uL * Flow cytometry showed CD4/CD8 ratio of 1.0