T-cell selection

Sakaguchi N, Takahashi T, Hata H, et al. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 2003 426(6965) 454 160. 

Finally, in this brief overview of lymphocyte defects, mention should be made of mutations affecting major histocompatibility-complex (MHC) Class II molecules. These mutations affect a multiprotein transcription factor complex that regulates the expression of MHC Class II molecules (121). Affected patients have undetectable levels of MHC Class II antigens HLA-DP, DQ, and DR on the surface of monocytes and B cells. Lack of these antigen-presenting molecules leads to impaired immune response. Affected individuals have moderate lymphopenia with a severely reduced number of CD4+ T cells and normal or increased numbers of CD8+ T cells. Since MHC molecules in the thymic epithelium play a key role in positive and negative selection of primitive T cells, selection of competent T cells is also affected in the absence of MHC Class II antigens. 

Picca CC, Larkin III J, Boesteanu A, Lerman MA, Rankin AL, Caton AJ. 2006. Role of TCR specificity in CD4+CD25+ regulatory T cell selection. Immunol Rev. 212 74-85. 

Figure 33.40. T-Cell Selection. A population of thymocytes is subjected first to positive selection to remove cells that express T-cell receptors that will not bind to MHC proteins expressed by the individual organism. The surviving cells are then subjected to negative selection to remove cells that bind strongly to MHC complexes bound to self-peptides.

Exclude compounds from further consideration that affect proliferation of unstimulated PBMC. Depending on the specific function of the PTP of interest in T cells, select compounds for further consideration accordingly. For instance, if the PTP plays an oncogenic role (like SHP2 (PTPNll) in various leukemias), select compounds that inhibit proliferation. If, on the other hand the, PTP inhibits T cell activation and is implicated in immunodeficiency, then select inhibitors that augment T cell activation/ proliferation. 

Immunophenotypic markers of monoclonal T-cell proliferations have not been identified. However, subtle alterations in broadly active T-cell selective ( pan-T-cell ) determinants may be helpful in selected cases. Cutaneous T-cell lymphomas (CTCL) characteristically express aberrant phenotypes, represented either by the relative absence of the pan-T-cell markers CD3, CDS, CD43, and CD7 (especially the last of those) or by the concordant expression or loss of both CD4 and CDS (Fig. 13.19).i 454 xhose results are not expected in most mature reactive (benign) T-cell populations. 455,156 Unfortunately, some examples of CTCL fail to exhibit aberrant phenotypes, limiting the value of these attributes in the separation of such lymphomas from T-cell-rich dermatitides,i 455 and, conversely,... 

In the defense mechanisms of the immnne system, helper T cell activation is essential for the initiation of a protective immnne response to pathogens and tumors. HLA-DR, the predommant isotype of the human class II major histocompatibility complex (MHC), plays a central role in helper T cell selection and activation. HLA-DR proteins bind peptide fragments derived from protein antigens and display them on the surface of antigen-presenting cells (APC) for interaction with antigen-specific receptors of T lymphocytes. 

Recent studies using the T-cell-selective agent cyclosporin A (CsA) have shown promising results in the management of steroid-dependent asthma. Trials of CsA treatment in steroid-dependent asthma have resulted in improved lung function, a reduction in asthma exacerbations, and a reduction of IL-2 and IL-2 receptor expression and the transcription and translation of mRNA for IL-5 and GM-CSF in CD4+ T cells (349). 

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