Abstract
Although the observation of major histocompatibility complex II (MHCII) receptors on T cells is longstanding, the explanation for this occurrence remains enigmatic. Reports of an inducible, endogenous expression exist, as do studies demonstrating a protein acquisition from other cells by mechanisms including vesicle transfer. Irrespective of origin, the presence of the human MHCII isotype, human leukocyte antigen DR (HLA-DR), potentially identifies a regulatory T cell population. Using an allogeneic mixed lymphocyte culture (MLC) to induce an antigen-specific immune response, the role of antigen-presenting cells (APCs) for the presence of HLA-DR on cluster of differentiation 3(CD3)+ CD4+ T cells was evaluated. Moreover, a functional phenotype was established for these T cells. It was demonstrated that APCs were essential for HLA-DR on CD3+ CD4+ T cells. Additionally, a regulatory T cell phenotype was induced in CD3+ CD4+ HLA-DR+ responder T cells with an expression of CD25, CTLA-4, CD62L, PD-1, and TNFRII. This phenotype was induced both with and without physical T cell:APC contact, which could reveal novel indications about its functionality. To further investigate contact-independent communication, a phenotype of the small cell-derived vesicles from the MLCs was determined. Yet heterogeneous, this vesicle phenotype displayed contact-dependent differences, providing clues about their intended function in cellular communication.
Highlights
The expression of major histocompatibility complex II (MHCII) is essential for the specificity of the adaptive immune system
This may explain the percentage-wise increase in CD3+ CD4+ human leukocyte antigen DR (HLA-DR)+ T cells in the responder control, when compared to baseline. This signifies that an actual cellular response was induced in both mixed lymphocyte culture (MLC) scenarios. To further support this observation, we demonstrated that the presence of HLA-DR on CD3+ CD4+ T cells could not be induced by activation stimuli, when antigen-presenting cells (APCs) were absent (Figure 4)
Since a cellular response was seemingly induced in both the contact-dependent and –independent MLC, we addressed yet another aspect relating to the physical T cell:APC contact and T cell activation
Summary
The expression of major histocompatibility complex II (MHCII) is essential for the specificity of the adaptive immune system. The T cell receptor (TCR) of CD4+ T cells interacts with the cognate peptide-MHCII complexes on antigen-presenting cells (APCs), activating the T cells. The constitutive expression of MHCII is limited to professional APCs, MHCII has for more than four decades been observed on T cells [1–4]. The most frequently expressed MHCII molecule in humans, the human leukocyte antigen DR (HLA-DR), is commonly used as a marker for T cell activation [5–7]. It remains a subject of discussion, whether the presence of MHCII on T cells is explained by an endogenous protein synthesis or by an acquisition from adjacent cells. The functional consequences of MHCII on T cells are still poorly understood
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