Dual T cell receptor T cells have a decreased sensitivity to physiological ligands due to reduced density of each T cell receptor

Abstract

A considerable fraction of T cells express two distinct T cell receptors (TCR), mainly due to expression of two TCR alpha chains. It has been suggested that such dual-TCR cells could have a role in autoimmunity. However, as such cells express less of each TCR, they could be less sensitive to their physiological ligand, i.e. peptide plus major histocompatibility complex molecules (MHC). We tested this hypothesis in a transgenic TCR model in which most T cells express different amounts of the transgene-encoded TCR, due to expression of endogenous TCR alpha chains. Five Th1 clones derived from lambda2(315) immunoglobulin light chain-specific TCR-transgenic mice expressed different levels of the transgene-encoded TCR, ranging from approximately 10,000 to approximately 50,000 TCR per cell. Cytosolic Ca2+ mobilization in single T cells from these clones elicited by lambda2(315) peptide-pulsed, I-Ed-expressing antigen-presenting cells, correlated linearly with the relative transgene-encoded TCR expression. The peptide requirement for half-maximal T cell proliferation showed a similar correlation, with low TCR levels requiring higher peptide concentration. Corroborative evidence was obtained by deployment of short-term polyclonal CD4+ lines from TCR-transgenic mice. Such lines had reduced early (Ca2+ mobilization) and late (lymphokine and proliferation) responses, compared with T cell lines from recombination-deficient TCR-transgenic severe combined immunodeficiency mice (which express only a single transgene-encoded TCR). Taken together, the Ca2+ responses increase gradually with increasing TCR expression per cell, similar to the previously described analog Ca2+ signaling elicited by increasing amounts of peptide/MHC [Røtnes et al., Eur. J. Immunol. 1994. 24: 851]. Surprisingly small reductions in TCR expression per cell reduce T cell responsiveness. This suggests that dual-TCR T cells are immunologically less effective than single-TCR T cells.

Functional balance between T cell chimeric receptor density and tumor associated antigen density: CTL mediated cytolysis and lymphokine production

“…1 The different T lymphocyte effector responses that can be elicited, ie quality and magnitude of the response, depend on the density of the T lymphocyte receptors as well as on target cell density. [10][11][12][13][14] A detailed understanding of antigen-receptor/antigen relationships is important for the efficient generation and expansion of optimally reactive, tumor-specific CTLs for immunotherapy, since adoptive transfer of tumor-specific CTLs has shown significant clinical benefit. 15,18 However, tumor-specific CTLs are difficult to isolate from cancer patients and their expansion to therapeutic numbers is time-consuming and the succes rate unpredictable.…”

“…14,30 The few reports available in the literature on the functional balance between TCR density and T lymphocyte response to antigens show that a decrease in TCR density results in reduced T lymphocyte responses. 11,13 Hence, quality and quantity of T lymphocyte responses depend on and differ in (1) required thresholds of TCR occupancies; (2) antigen densities; and (3) antigen potencies. Different T lymphocyte responses may require…”

“…Chimeric receptor and TAA densities also co-determine levels of T lymphocyte IFN-␥ and TNF-␣ production Individual CTLs can exercise distinct biological responses as a function of percentage of TCR occupancy, 8,[10][11][12][13][14] which in turn is determined by ligand density and potency. 12 Therefore we studied the capacity of chRec LOW and HIGH POS T lymphocytes to secrete INF-␥ and TNF-␣ in response to G250 TAA LOW and HIGH POS RCCs.…”

“…[11][12][13][14]31 During the preparation of this manuscript we became aware of the data recently published by Alvarez and Russell, 32 who used a model system using Jurkat T cells with tetracycline-regulatable ch-Rec densities to study their level of IL-2 response as a function of plastic-coated antigen density. They concluded that Jurkat T cells can be engineered to discriminate…”

“…8,[10][11][12][13] The limited data that are available on the effect of low versus high TCR densities on antigen reactive T lymphocyte responses show a correlation with T lymphocyte activities. 11,13,14 A detailed understanding of the functional balance between TCR and TAA densities is therefore essential for the generation of optimally antitumor reactive T lymphocytes for cancer gene-immunotherapy now that adoptive transfer of tumor-specific CTLs to patients has demonstrated clinical benefit. However, specific CTLs from patients are difficult to isolate and cumbersome to expand to therapeutic numbers and this critically limits their clinical application.…”