Spontaneous internalization of Class I major histocompatibility complex molecules in T lymphoid cells.

Under optimal Ag stimulation, CTL become functional effector and memory T cells. Professional APCs (pAPC) are considered essential for the activation of CTL, due to their unique capacity to provide costimulation and present exogenous Ags through MHC class I molecules. In this study, we report a novel means by which Th lymphocytes acquire and present MHC class I determinants to naive CTL. Although previous studies have looked at T cell Ag presentation to activated T cells, this study presents the first example of Ag presentation by Th cells to naive CTL. We report that activated Th cells can function as effective pAPC for CTL. Our results show that: 1) In addition to acquisition of cell surface molecules, including MHC class I/peptide complexes, from pAPC, Th cells can acquire and present MHC class I-binding peptides through TCR-MHC class II interactions with pAPC; 2) the acquired Ag can be functionally presented to CTL; and 3) Ag presentation by Th cells induces naive CTL to proliferate and preferentially differentiate into cells that phenotypically and functionally resemble central memory T cells. These findings suggest a novel role of Th cells as pAPC for the development of memory immune responses.

Section: Discussionmentioning

confidence: 99%

Direct Cross-Priming by Th Lymphocytes Generates Memory Cytotoxic T Cell Responses

Kennedy

Undale

Kieper

et al. 2005

“…T cells activated with Con A or in an MLR spontaneously internalize their MHC-I molecules into endosome-like vesicles with a t 1/2 of ϳ1 h and recycle them from these vesicles to the cell surface with a t 1/2 of ϳ20 min (24,26,27). MHC-I containing a p H can be recycled to the cell surface still containing the p H (25).…”

Section: Discussionmentioning

confidence: 99%

“…Surface expression of MHC-I is also lost through internalization (20). Internalization of MHC-I occurs constitutively on activated lymphoid cells (23)(24)(25)(26)(27)). It appears that intact molecules are recycled to the cell surface and denatured molecules are shunted to a lysosomal pathway.…”

Section: Stability Ofmentioning

confidence: 99%

Stability of Surface H-2Kb, H-2Db, and Peptide-Receptive H-2Kb on Splenocytes

Miller

2001

We have used flow cytometry to study the stability and peptide-binding capability of MHC class I (MHC-I) on the surface of normal C57BL/6 mouse T lymphoblasts. The MHC-I molecules on each cell are nearly evenly divided into two populations with mean half-life values of ∼1 and 20 h. Our observations suggest that members of the later contain peptide bound with medium to high affinity. Cell surface MHC-I molecules capable of binding exogenous peptide (thus, “peptide-receptive”) belong almost entirely to the less stable population. Before exogenous peptide can bind, MHC-I must undergo a change, probably loss of a very low affinity peptide. For MHC-I-Kb, we found that the maximum rate for binding of exogenous peptide corresponds to a t1/2 value of 12 min. To maintain the 50:50 steady-state distribution of long- vs short-lived MHC-I molecules on the cell surface, ∼20 short-lived molecules must be exported to the cell surface for each long-lived molecule.

“…Endocytosis of MHC-I molecules has long been recognized, and occurs in a variety of different cell types (5)(6)(7)(8)(9). The process has biological implications for endosomal and lysosomal peptide loading and display, with the latter event designated as cross-presentation (14,33).…”

Section: Discussionmentioning

confidence: 99%

“…The rate of spontaneous endocytosis of MHC-I molecules is higher in lymphoid T cells and monocytes than in B cells and can be induced by activation of protein kinase C-regulated pathways (5)(6)(7)(8)(9). Zuniga and colleagues (5) were the first to report that endocytosis of MHC-I molecules required the cytoplasmic domain and suggested that a conformational change was required for endocytosis.…”

mentioning

confidence: 99%

Lack of Tyrosine 320 Impairs Spontaneous Endocytosis and Enhances Release of HLA-B27 Molecules

Santos

Antoniou

Sampaio³

et al. 2006

Several lines of evidence suggest that endocytosis of MHC class I molecules requires conserved motifs within the cytoplasmic domain. In this study, we show, in the C58 rat thymoma cell line transfected with HLA-B27 molecules, that replacement of the highly conserved tyrosine (Tyr320) in the cytoplasmic domain of HLA-B27 does not hamper cell surface expression of β2-microglobulin H chain heterodimers or formation of misfolded molecules. However, Tyr320 replacement markedly impairs spontaneous endocytosis of HLA-B27. Although wild-type molecules are mostly internalized via endosomal compartments, Tyr320-mutated molecules remain at the plasma membrane in which partial colocalization with endogenous transferrin receptors can be observed, also impairing their endocytosis. Finally, we show that Tyr320 substitution enhances release of cleaved forms of HLA-B27 from the cell surface. These studies show for the first time that Tyr320 is most likely part of a cytoplasmic sorting motif involved in spontaneous endocytosis and shedding of MHC class I molecules.