Adaptable TCR Avidity Thresholds for Negative Selection

Stojakovic, Milica; Salazar-Fontana, Laura I.; Tatari-Calderone, Zohreh; Badovinac, Vladimir P.; Santori, Fabio R.; Kovalovsky, Damián; Sant’Angelo, Derek B.; Harty, John T.; Vukmanović, Stanislav

doi:10.4049/jimmunol.181.10.6770

Cited by 8 publications

(19 citation statements)

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“…MTB TCRβ transgenic mice display globally increased avidity for peptide/MHC complexes due to stronger interactions with MHC molecules [23]. As previously reported, higher levels of CD5 with fewer cell surface TCR/CD3 were found in MTB than in WT mice (Figure 5A).…”

Section: Resultssupporting

confidence: 78%

“…Because of day-to-day experimental variations and the use of antibodies conjugated to different fluorochromes, we calculated ratios of mean fluorescence intensities (MFI) obtained in spleen cells from paired old and young mice, as previously described [23]. Significant ( p < 0.0001) reduction of CD3 levels was observed in all old mice, while the levels of CD5, although overall significantly ( p = 0.0127) reduced, were heterogenous (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

“…Lower levels of CD3 and higher levels of CD5 are indicators of high functional TCR avidity [21,23], and chronic high-avidity TCR stimulation leads to production of IL-10 [34-37]. We therefore sought to determine whether aging immune system is prone to produce IL-10.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, CD3 and CD5 levels can serve as indicator of the strength of signal perception by T cells, and if the levels of self-peptide/MHC are constant, the major determinant of the signal magnitude generated is the affinity/avidity of the TCR for self-peptide/MHC complexes. Taking advantage of the fact that levels of CD5 and TCR/CD3 expression can be used to predict relative TCR avidity [21], we have shown that relative levels of these two molecules could be used as markers of overall avidity of the TCR repertoire [23]. …”

Section: Introductionmentioning

confidence: 99%

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Age-related accumulation of T cells with markers of relatively stronger autoreactivity leads to functional erosion of T cells

et al. 2012

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BackgroundThymic involution is a prominent characteristic of an aging immune system. When thymic function is reduced/absent, the peripheral T cell pool is subject to the laws of peripheral T cell homeostasis that favor survival/expansion of T cell receptors with relatively higher functional avidity for self-peptide/MHC complexes. Due to difficulties in assessing the TCR avidity in polyclonal population of T cells, it is currently not known whether high avidity T cells preferentially survive in aging individuals, and what impact this might have on the function of the immune system and development of autoimmune diseases.ResultsThe phenotype of T cells from aged mice (18-24 months) indicating functional TCR avidity (CD3 and CD5 expression) correlates with the level of preserved thymic function. In mice with moderate thymic output (> 30% of peripheral CD62Lhi T cells), T cells displayed CD3lowCD5hi phenotype characteristic for high functional avidity. In old mice with drastically low numbers of CD62Lhi T cells reduced CD5 levels were found. After adult thymectomy, T cells of young mice developed CD3lowCD5hi phenotype, followed by a CD3lowCD5low phenotype. Spleens of old mice with the CD3low/CD5hi T cell phenotype displayed increased levels of IL-10 mRNA, and their T cells could be induced to secrete IL-10 in vitro. In contrast, downmodulation of CD5 was accompanied with reduced IL-10 expression and impaired anti-CD3 induced proliferation. Irrespective of the CD3/CD5 phenotype, reduced severity of experimental allergic myelitis occurred in old mice. In MTB TCRβ transgenic mice that display globally elevated TCR avidity for self peptide/MHC, identical change patterns occurred, only at an accelerated pace.ConclusionsThese findings suggest that age-associated dysfunctions of the immune system could in part be due to functional erosion of T cells devised to protect the hosts from the prolonged exposure to T cells with high-avidity for self.

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Section: Resultssupporting

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Age-related accumulation of T cells with markers of relatively stronger autoreactivity leads to functional erosion of T cells

et al. 2012

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“…In the thymus, T cells are selected according to their avidity for self-peptide/MHC complexes. The TCR must be able to recognize self-peptide/MHC complexes with enough affinity to transduce a signal during positive selection while not binding so tightly that they are negatively selected [4–6]. TCR avidity and signal strength plays a key role in T cell function (calcium signaling, cytokine production, T cell proliferation and differentiation) [7–9].…”

Section: Introductionmentioning

confidence: 99%

Naïve helper T cells with high CD5 expression have increased calcium signaling

et al. 2017

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The adaptive immune response is orchestrated by T helper cells and their function is dependent upon interactions between the T cell receptor (TCR), peptide MHC (pMHC) and co-receptors. TCR-pMHC interactions initiate calcium signaling cascades which determine T cell activation, survival, proliferation and differentiation. CD5 is a co-receptor that plays an important role in regulating T cell signaling and fate during thymocyte education. CD5 surface expression on mature single positive thymocytes correlates with the TCR signal strength for positive selecting self-ligands. CD5 also plays a role in T cell function after thymic development is complete. Peripheral T cells with higher CD5 expression respond better to foreign antigen than those with lower CD5 expression and CD5-high T cells are enriched in memory populations. In our study, we examined the role of CD5 expression and calcium signaling in the primary response of T cells using two Listeria monocytogenes specific T helper cells (LLO118 and LLO56). These T cells recognize the same immunodominant epitope (LLO190-205) of L. monocytogenes and have divergent primary and secondary responses and different levels of CD5 expression. We found that each T cell has unique calcium mobilization in response to in vitro stimulation with LLO190-205 and that CD5 expression levels in these cells changed over time following stimulation. LLO56 naïve T helper cells, which expresses higher levels of CD5, have higher calcium mobilization than naïve LLO118 T cells. Three days after in vitro stimulation, LLO118 T cells had more robust calcium mobilization than LLO56 and there were no differences in calcium mobilization 8 days after in vitro stimulation. To further evaluate the role of CD5, we measured calcium signaling in CD5 knockout LLO118 and LLO56 T cells at these three time points and found that CD5 plays a significant role in promoting the calcium signaling of naïve CD5-high LLO56 T cells.

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Effective adoptive therapy of tap-deficient lymphoma using diverse high avidity alloreactive T cells

Popmihajlov

Santori

Gebreselassie

et al. 2009

Cancer Immunol Immunother

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High avidity for antigen and diversity of T cell receptor (TCR) repertoire are essential for effective immunity against cancer. We have previously created a transgenic mouse strain with increased TCR avidity in a diverse T cell population. In this report, we show that strong alloreactive responses of transgenic T cells against targets with low MHC class I expression can be used for effective adoptive transfer of tumor immunity in vivo. Alloreactive transgenic T cells could be an effective therapeutic approach counteracting tumor evasion of the immune system.

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Adaptable TCR Avidity Thresholds for Negative Selection

Cited by 8 publications

References 47 publications

Age-related accumulation of T cells with markers of relatively stronger autoreactivity leads to functional erosion of T cells

Age-related accumulation of T cells with markers of relatively stronger autoreactivity leads to functional erosion of T cells

Naïve helper T cells with high CD5 expression have increased calcium signaling

Effective adoptive therapy of tap-deficient lymphoma using diverse high avidity alloreactive T cells

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