Thymus‐leukemia antigen (TL) as a major histocompatibility complex (MHC) class Ib molecule and tumor‐specific antigen

Abstract

Mouse thymus-leukemia antigens (TL) belong to the family of major histocompatibility complex (MHC) class Ib antigens and have a unique mode of expression, i.e., in contrast to other MHC class Ib or Ia antigens, they are found restricted to the intestines in all mouse strains, but also in the thymus of certain strains (TL + strains). Nevertheless, a proportion of T lymphomas/leukemias in strains that do not express TL in the thymus (TL -strains) feature TL as a tumor antigen. TL was originally defined serologically, but subsequently we have succeeded in generating T cell receptor (TCR) α α α αβ β β β and γ γ γ γδ δ δ δ cytotoxic T lymphocytes (CTL) recognizing TL. By use of TL tetramers free from peptides and transfectants expressing various TL/H-2 chimeric molecules, we have been able to show that TL-specific CTL recognize the α α α α1/ α α α α2 domain of TL without any additional antigen molecules. We previously reported that one of TL's functions in the thymus is positive selection of TCRγ γ γ γδ δ δ δ CTL. Recent studies with TL tetramers revealed that they can bind to normal intestinal intraepithelial lymphocytes (iIEL) and thymocytes in a CD8-dependent, but TCR/CD3-independent manner, while their binding to TL-specific CTL is TCR/CD3-and CD8-dependent. The possible significance of these findings in relation to the roles of TL in the intestines is discussed. ouse thymus-leukemia antigens (TL) are major histocompatibility complex (MHC) class Ib (or nonclassical MHC class I) molecules encoded by closely related genes in the T region of mouse MHC. 1-5) TL genes have overall structures similar to MHC class Ia (classical MHC class I) genes, and show high homology among themselves, but they are only distantly related to other MHC class Ia and Ib genes, indicating the operation of natural selection to preserve the function of TL. 6)The products of TL genes are glycoproteins with molecular weights of approximately 45,000 daltons [7][8][9] and are expressed on the cell surface with β 2 -microglobulin (β 2 M), but they can be independently expressed transporters associated with antigen processing (TAP). 4,[10][11][12] A recent crystallographical analysis yielded the important finding that T18 d -TL has no antigen-binding groove wide enough to accommodate a peptide or lipid antigen, 13) in contrast to other MHC class Ia and Ib products. In normal mice, the expression of TL is restricted to the intestines in all mouse strains, but also the thymus of TL + strains (Fig. 1), 1,14,15) suggesting that TL plays a specialized role(s) in these organs, especially in the intestines. TL was originally described in 1963 as a serologically defined tumor-specific antigen, [16][17][18] since a proportion of T lymphomas/leukemias originating even from TL -strains (which do not express TL in the thymus) express TL (Fig. 1). We recently demonstrated that TL can also serve as a transplantation and tumor rejection antigen for T cells 19,20) and that both T cell receptor (TCR) αβ and γδ cytotoxic T lymphocytes (CTL) specific for TL can kill...

Lysis-on-Chip of Single Target Cells following Forced Interaction with CTLs or NK Cells on a Dielectrophoresis-Based Array

“…Commercially available systems (http://www.siliconbiosystems.com) have extended these limits to 40,000 independently routable cages. To improve throughput to an extent that would make the assay useful to test nonclonal target and effector cells obtained from live organisms, the preliminary enrichment of CTL and NK cell populations may be required, by either Ab or tetramer staining (38,39), followed by sorting (40). This exemplifies the complementary nature of DEPArray and classical techniques.…”

Immunity against mouse thymus‐leukemia antigen (TL) protects against development of lymphomas induced by a chemical carcinogen, N‐butyl‐N‐nitrosourea

“…[5][6][7][8] In addition, their possible roles in situ have been elucidated to a certain extent, [7][8][9] though many issues remain to be clarified. Although TL − strains (e.g., C57BL/6 (B6) and C3H/He (C3H)) do not express TL in the thymus, a proportion of T lymphomas originating in these mice express TL as a serologically defined tumor antigen.…”

“…[1][2][3][4] Recent studies by us and others showed that TL molecules bind with CD8αα + intestinal intraepithelial lymphocytes, CD8 + thymocytes and CD8αα + peripheral T lymphocytes. [5][6][7][8] In addition, their possible roles in situ have been elucidated to a certain extent, [7][8][9] though many issues remain to be clarified. Although TL − strains (e.g., C57BL/6 (B6) and C3H/He (C3H)) do not express TL in the thymus, a proportion of T lymphomas originating in these mice express TL as a serologically defined tumor antigen.…”