Overview of T-cell and NK-cell differentiation and the putative histogenetic derivation of the major subtypes of mature T- and NK-cell neoplasms.

Mature T cells derived from precursor lymphoblasts in the thymus are genetically characterized by functional rearrangement of the T-cell receptor (TCR) genes. Based on the structure of the TCR, two classes of T cells are recognized: αβ and γδ; both express CD3. γδ T cells are CD4^–CD8^– or less often CD4^–CD8⁺, they comprise < 5% of T cells in the peripheral blood and show a restricted distribution mainly to the epithelia where they are involved in mucosal immunity, and to the red pulp of the spleen. αβ T cells are divided into CD4⁺ (mainly helper, with Th1 or Th2 profile of cytokine-secretion) and CD8⁺ (mainly cytotoxic) subsets. Mature naive T cells are found in the thymic medulla, in the circulation and in the paracortex of lymph nodes. Antigen-dependent reaction occurs in the paracortex of lymph nodes. From the immunoblastic reaction come antigen-specific T cells of either CD4 or CD8 type, as well as memory cells, that may recirculate and home to peripheral tissues.

NK cells derived from a bone marrow precursor are distinguished by the absence of TCR rearrangement and membrane TCR expression. NK cells share some markers with T cells as they can express CD2, CD7, CD43, CD45RO, and cytoplasmic (but not surface) CD3. NK cells are usually CD4^–CD8^– but may be CD8⁺, and they express one or several of the “NK-associated” antigens (CD11b, CD16, CD56, CD57, NK receptors), none of which, except perhaps CD16, is specific since they can also be expressed by some T cells. Both NK cells and activated cytotoxic T cells express cytotoxic proteins, T-cell intracellular antigen (TIA)-1, perforin, and granzymeB.

Functionally, the majority of T cells are part of the specific/adaptive immune system and recognize the antigen in a MHC-restricted fashion in the presence of an antigen-presenting cell, whereas NK cells, a subset of the γδ T cells and a minor subset of αβ T cells are part of the innate immunity, i.e., the recognition of antigens occurs through surface receptors independently of a MHC-restricted presentation, involving NK receptors and toll-like receptors.

Mature T/NK-cell lymphomas manifest the immunophenotypic and genetic features of post-thymic T lymphocytes or mature NK cells. T-PLL is thought to derive from naive T cells at a stage intermediate between thymic lymphoblasts and mature naive T cells. NK cells are the cell of origin for aggressive or chronic NK cell leukemias, and give rise to NK-cell lymphomas in tissues, usually in the nasal area. The majority of extranodal T-cell lymphomas derive from cytotoxic T cells; one exception is mycosis fungoides derived from effector CD4⁺ cells with cutaneous homing properties. γδ T cells give rise to most cases of hepatosplenic T-cell lymphomas as well as a subset of cutaneous T-cell lymphomas. Enteropathy-associated T-cell lymphoma derives from intraepithelial—usually αβ—T cells of the intestine. Adult T-cell lymphoma/leukemia associated with HTLV1 infection is a neoplasm derived from a peculiar subset of CD4⁺ T cells with a frequent regulatory phenotype (CD25⁺ FoxP3⁺). The cellular derivation of nodal-based T-cell lymphomas will be discussed later in the text.

Abbreviations: AITL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large cell lymphoma; LGL, large granular lymphocytic; HTLV, human T-cell leukemia virus; PLL, prolymphocytic leukemia; PTCL, NOS: peripheral T-cell lymphoma, not otherwise specified; TCL, T-cell lymphoma.