T Cells Survey the Stability of the Self: A Testable Hypothesis on the Homeostatic Role of TCR-MHC Interactions

Bakács, Tibor; Mehrishi, J.N.; Szabados, Tamás; Varga, László; Szabó, Miklós; Tusnády, Gábor

doi:10.1159/000103282

Cited by 11 publications

(11 citation statements)

References 170 publications

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“…When this does occur, the theory gains credibility and robustness. Our "one-signal" T cell activation theory (Bakacs et al, 2007) predicted the continuous presence of activated self-reactive T cells. This is because T cells physiologically are kept alive by low affinity complementary TCR-MHC interactions between auto-reactive T cells and host cells.…”

Section: Introductionmentioning

confidence: 94%

Anti-CTLA-4 therapy may have mechanisms similar to those occurring in inherited human CTLA4 haploinsufficiency

Bakács

Mehrishi

2015

Immunobiology

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Section: Introductionmentioning

confidence: 94%

Anti-CTLA-4 therapy may have mechanisms similar to those occurring in inherited human CTLA4 haploinsufficiency

Bakács

Mehrishi

2015

Immunobiology

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“…Since immune cells require regular stimulation for survival, 56 Bakacs et al proposed that self-antigens, from time to time, activate T cells through an internal dialogue via a one-signal mechanism. 28 Temporarily activated T cells express CTLA-4, which is blocked by anti-CTLA-4 antibodies, not only on tumour-specific T cells, but also on all activated T cells. 57 As predicted by Weber, 25 immune checkpoint blockade cannot be restricted to the targeted tumour-specific T cell population, such that this blockade induces an uncontrolled pan T cell activation, tolerance to healthy self-tissues will be compromised.…”

Section: Iatrogenic Ctla-4 Blockade Turns Physiologic Autoimmunit Ymentioning

confidence: 99%

“…Since immune cells require regular stimulation for survival, Bakacs et al proposed that self‐antigens, from time to time, activate T cells through an internal dialogue via a one‐signal mechanism . Temporarily activated T cells express CTLA‐4, which is blocked by anti‐CTLA‐4 antibodies, not only on tumour‐specific T cells, but also on all activated T cells .…”

Section: Iatrogenic Ctla‐4 Blockade Turns Physiologic Autoimmunity Inmentioning

confidence: 99%

“…We would suggest that the widespread, dose-dependent irAEs of ipilimumab can best be explained by the view that all T cells possess self-reactivity. [27][28][29][30][31] The 'tonic' signal 1 (TCR signal), generated by positively selecting self-peptide/major histocompatibility complex (MHC), promotes activation and homeostatic survival of T cells in the periphery. Furthermore, there is evidence for control of such tonic TCR signals by co-inhibitors.…”

Section: Blockade Induces An Uncontrolled T Cell Activationmentioning

confidence: 99%

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Exploiting autoimmunity unleashed by low‐dose immune checkpoint blockade to treat advanced cancer

Bakács¹,

Moss²,

Kleef³

et al. 2019

Scand J Immunol

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As a result of the cancer immunotherapy revolution, more than 2000 immuno‐oncology agents are currently being tested or are in use to improve responses. Not unexpectedly, the 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo for their development of cancer therapy by the blockade of co‐inhibitory signals. Unfortunately, manipulation of the co‐inhibitory receptors has also resulted in a safety issue: widespread iatrogenic immune‐related adverse events (irAEs). Autoimmunity is emerging as the nemesis of immunotherapy. Originally, it was assumed that CTLA‐4 blockade selectively targets T cells relevant to the antitumour immune response. However, an uncontrolled pan T cell activation was induced compromising tolerance to healthy self‐tissues. The irAEs are very similar to that of a chronic graft‐versus‐host‐disease (GVHD) reaction following allogeneic bone marrow transplantation (BMT). We hypothesized that ipilimumab induced a graft‐versus‐malignancy (GVM) effect, which eradicated metastatic melanoma in a minority of patients, but also involved an auto‐GVHD reaction that resulted in widespread autoimmunity in the majority. Therefore, we argued for a profound theoretical point against the consensus of experts. The task is not to desperately put the genie back in the bottle by immune‐suppressive treatments, but instead to harness the autoimmune forces. In this way, the same goal could be achieved by an antibody as by the adoptive transfer of alloreactive donor lymphocytes, but without severe GVHD. The proof‐of‐principle of a low‐dose‐combination immune checkpoint therapy, consisting only of approved drugs and treatments, was demonstrated in 111 stage IV cancer patients.

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“…Therefore, inhibition of metastases at secondary sites by fostering maintenance of immune and tissue homeostasis offers promising approach for cancer therapy when dormant malignant disease might be suspected to occur. In order to prevent the kick-start growth of micrometastases by surgical resection of the primary tumour, we propose a predictably feasible new 'physiological' therapy approach, which is based on the homeostatic role of T cells model [23]. We believe that crucially the virtue of our hypothesis is that the evolutionary pressure driving the creation of a T cell receptor (TCR) repertoire was primarily the homeostatic surveillance of the genome.…”

Section: Presentation Of the Hypothesismentioning

confidence: 99%

Breast and other cancer dormancy as a therapeutic endpoint: speculative recombinant T cell receptor ligand (RTL) adjuvant therapy worth considering?

Bakács

Mehrishi

2010

BMC Cancer

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BackgroundMost individuals who died of trauma were found to harbour microscopic primary cancers at autopsies. Surgical excision of the primary tumour, unfortunately, seems to disturb tumour dormancy in over half of all metastatic relapses.Presentation of the hypothesisA recently developed immune model suggested that the evolutionary pressure driving the creation of a T cell receptor repertoire was primarily the homeostatic surveillance of the genome. The model is based on the homeostatic role of T cells, suggesting that molecular complementarity between the positively selected T cell receptors and the self peptide-presenting major histocompatibility complex molecules establishes and regulates homeostasis, strictly limiting variations of its components. The repertoire is maintained by continuous peripheral stimulation via soluble forms of self-peptide-presenting major histocompatibility complex molecules governed by the law of mass action. The model states that foreign peptides inhibit the complementary interactions between the major histocompatibility complexes and T cell receptors. Since the vast majority of clinically detected cancers present self-peptides the model assumes that tumour cells are, paradoxically, under homeostatic T cell control.The novelty of our hypothesis therefore is that resection of the primary tumour mass is perceived as loss of 'normal' tissue cells. Consequently, T cells striving to reconstitute homeostasis stimulate rather than inhibit the growth of dormant tumour cells and avascular micrometastases. Here we suggest that such kick-start growths could be prevented by a recombinant T cell receptor ligand therapy that modifies T cell behaviour through a partial activation mechanism.Testing the hypothesisThe homeostatic T cell regulation of tumours can be tested in a tri-transgenic mice model engineered to express potent oncogenes in a doxycycline-dependent manner. We suggest seeding dissociated, untransformed mammary cells from doxycycline naïve mice into the lungs of two mice groups: one carries mammary tumours, the other does not. Both recipient groups to be fed doxycycline in order to activate the oncogenes of the untransformed mammary cells in the lungs, where solitary nodules are expected to develop 6 weeks after injection. We expect that lung metastasis development will be stimulated following resection of the primary tumour mass compared to the tumour-free mice. A recombinant T cell receptor ligand therapy, starting at least one day before resection and continuing during the entire experimental period, would be able to prevent the stimulating effect of surgery.Implications of the hypothesisRecombinant T cell receptor ligand therapy of diagnosed cancer would keep all metastatic deposits microscopic for as long as the therapy is continued without limit and could be pursued as one method of cancer control. Improving the outcome of therapy by preventing the development of metastases is perhaps achievable more readily than curing patients with overt metastases.

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T Cells Survey the Stability of the Self: A Testable Hypothesis on the Homeostatic Role of TCR-MHC Interactions

Cited by 11 publications

References 170 publications

Anti-CTLA-4 therapy may have mechanisms similar to those occurring in inherited human CTLA4 haploinsufficiency

Anti-CTLA-4 therapy may have mechanisms similar to those occurring in inherited human CTLA4 haploinsufficiency

Exploiting autoimmunity unleashed by low‐dose immune checkpoint blockade to treat advanced cancer

Breast and other cancer dormancy as a therapeutic endpoint: speculative recombinant T cell receptor ligand (RTL) adjuvant therapy worth considering?

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