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Kim-1/Tim-1 and immune cells: shifting sands

2012; Elsevier BV; Volume: 81; Issue: 9 Linguagem: Inglês

10.1038/ki.2012.11

1523-1755

Takaharu Ichimura, Craig R. Brooks, Joseph V. Bonventre,

Pancreatitis Pathology and Treatment

Kim-1/Tim-1 is an apoptotic-cell phagocytosis and scavenger receptor that is most highly upregulated in proximal tubular epithelium in acute and chronic kidney injury. While Kim-1/Tim-1 has been proposed to be a costimulatory molecule for immune cells, its potential immunological role has been controversial. In the presence of very high epithelial cell expression, understanding the influence of immune cell Kim-1/Tim-1 expression in kidney injury relies on a better definition of its functional significance in immune cells and better characterization of antibodies used to probe function. Kim-1/Tim-1 is an apoptotic-cell phagocytosis and scavenger receptor that is most highly upregulated in proximal tubular epithelium in acute and chronic kidney injury. While Kim-1/Tim-1 has been proposed to be a costimulatory molecule for immune cells, its potential immunological role has been controversial. In the presence of very high epithelial cell expression, understanding the influence of immune cell Kim-1/Tim-1 expression in kidney injury relies on a better definition of its functional significance in immune cells and better characterization of antibodies used to probe function. Kidney injury molecule-1/T-cell immunoglobulin and mucin domain-containing protein-1 (KIM-1/TIM-1 in humans, Kim-1/Tim-1 in rodents) is a type 1 membrane receptor1.Bonventre J.V. Yang L. Kidney injury molecule-1.Curr Opin Crit Care. 2010; 16: 556-561Crossref PubMed Scopus (85) Google Scholar,2.Rennert P.D. Novel roles for TIM-1 in immunity and infection.Immunol Lett. 2011; 141: 28-35Crossref PubMed Scopus (48) Google Scholar that is the most highly upregulated protein in the proximal tubule of the injured kidney (Figure 1). It has also, to varying degrees, been reported to be expressed on immune cells.2.Rennert P.D. Novel roles for TIM-1 in immunity and infection.Immunol Lett. 2011; 141: 28-35Crossref PubMed Scopus (48) Google Scholar,3.Xiao S. Zhu B. Jin H. et al.Tim-1 stimulation of dendritic cells regulates the balance between effector and regulatory T cells.Eur J Immunol. 2011; 41: 1539-1549Crossref PubMed Scopus (42) Google Scholar In the kidney, Kim-1 is upregulated in a wide variety of human diseases and in various animal models.1.Bonventre J.V. Yang L. Kidney injury molecule-1.Curr Opin Crit Care. 2010; 16: 556-561Crossref PubMed Scopus (85) Google Scholar A large amount of KIM-1 protein is also shed into the urine, making it a useful urinary biomarker for kidney injury.1.Bonventre J.V. Yang L. Kidney injury molecule-1.Curr Opin Crit Care. 2010; 16: 556-561Crossref PubMed Scopus (85) Google Scholar Kim-1 functions as a phosphatidylserine receptor that recognizes and internalizes apoptotic cells.4.Ichimura T. Asseldonk E.J. Humphreys B.D. et al.Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells.J Clin Invest. 2008; 118: 1657-1668Crossref PubMed Scopus (555) Google Scholar Kim-1 also functions as a scavenger receptor, mediating the uptake of modified low-density lipoprotein and necrotic-cell debris.4.Ichimura T. Asseldonk E.J. Humphreys B.D. et al.Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells.J Clin Invest. 2008; 118: 1657-1668Crossref PubMed Scopus (555) Google Scholar Kim-1 expression transforms proximal tubular epithelial cells into semiprofessional phagocytes. In the immune system, Kim-1/Tim-1 has been implicated in activation of T-helper 2 (Th2), Th1, and Th17 differentiation.2.Rennert P.D. Novel roles for TIM-1 in immunity and infection.Immunol Lett. 2011; 141: 28-35Crossref PubMed Scopus (48) Google Scholar It has also been proposed to be an activating receptor in B cells, dendritic cells, and natural killer T cells.2.Rennert P.D. Novel roles for TIM-1 in immunity and infection.Immunol Lett. 2011; 141: 28-35Crossref PubMed Scopus (48) Google Scholar, 3.Xiao S. Zhu B. Jin H. et al.Tim-1 stimulation of dendritic cells regulates the balance between effector and regulatory T cells.Eur J Immunol. 2011; 41: 1539-1549Crossref PubMed Scopus (42) Google Scholar, 5.Wong S.H. Barlow J.L. Nabarro S. et al.Tim-1 is induced on germinal centre B cells through B-cell receptor signalling but is not essential for the germinal centre response.Immunology. 2010; 131: 77-88PubMed Google Scholar, 6.Ding Q. Yeung M. Camirand G. et al.Regulatory B cells are identified by expression of TIM-1 and can be induced through TIM-1 ligation to promote tolerance in mice.J Clin Invest. 2011; 121: 3645-3656Crossref PubMed Scopus (369) Google Scholar Many of the experiments that have led to these conclusions have relied on antibodies against Kim-1/Tim-1, which have been presumed to be agonists or antagonists, or Kim-1/Tim-1-Fc fusion proteins as key reagents.2.Rennert P.D. Novel roles for TIM-1 in immunity and infection.Immunol Lett. 2011; 141: 28-35Crossref PubMed Scopus (48) Google Scholar Nozaki and colleagues7.Nozaki Y. Nikolic-Paterson D.J. Snelgrove S.L. et al.Endogenous Tim-1 (Kim-1) promotes T-cell responses and cell-mediated injury in experimental crescentic glomerulonephritis.Kidney Int. 2012; 81: 844-855Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar (this issue) report that a low-avidity anti-Tim-1 antibody, RMT1-10, used as an antagonist of Kim-1/Tim-1, suppressed T-cell immune responses and glomerular/tubulointerstitial changes in a model of disease induced by anti-glomerular basement membrane globulin. (This antibody may not be identical to the commercially available antibody with the same name.8.Kane L. T cell Ig and mucin domain proteins and immunity.J Immunol. 2010; 184: 2743-2749Crossref PubMed Scopus (59) Google Scholar) Treatment with RMT1-10 reduced crescentic glomerulonephritis and Th1/Th17 cellular responses both in systemic immune cells and within the kidney while increasing renal Foxp3+ cell and interleukin-10 mRNA, characteristics of regulatory T cells and Th2 cells, respectively. Two other studies have recently demonstrated a partial protection of kidneys by the same RMT1-10 antibody in acute kidney injury induced by cisplatin or ischemia–reperfusion.9.Nozaki Y. Nikolic-Paterson D.J. Yagita H. et al.Tim-1 promotes cisplatin nephrotoxicity.Am J Physiol Renal Physiol. 2011; 301: F1098-F1104Crossref PubMed Scopus (41) Google Scholar,10.Rong S. Park J.K. Kirsch T. et al.The TIM-1:TIM-4 pathway enhances renal ischemia-reperfusion injury.J Am Soc Nephrol. 2011; 22: 484-495Crossref PubMed Scopus (39) Google Scholar The authors of these studies also concluded that Kim-1/Tim-1 mediated activation of detrimental T-cell and/or innate immune responses.9.Nozaki Y. Nikolic-Paterson D.J. Yagita H. et al.Tim-1 promotes cisplatin nephrotoxicity.Am J Physiol Renal Physiol. 2011; 301: F1098-F1104Crossref PubMed Scopus (41) Google Scholar,10.Rong S. Park J.K. Kirsch T. et al.The TIM-1:TIM-4 pathway enhances renal ischemia-reperfusion injury.J Am Soc Nephrol. 2011; 22: 484-495Crossref PubMed Scopus (39) Google Scholar Activation of injurious Th1 cells was inhibited or Th1-related cytokines were diminished by RMT1-10. In the study by Nozaki and colleagues,7.Nozaki Y. Nikolic-Paterson D.J. Snelgrove S.L. et al.Endogenous Tim-1 (Kim-1) promotes T-cell responses and cell-mediated injury in experimental crescentic glomerulonephritis.Kidney Int. 2012; 81: 844-855Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar however, a significant portion of the injected RMT1-10 antibody was shown to accumulate at proximal tubules where Kim-1 is expressed. Given the very high expression of Kim-1/Tim-1 in the kidney relative to its expression in immune cells, care must be taken in interpreting the results achieved with the antibody (Figure 1). Questions have also been raised concerning the RMT1-10 antibody. RMT1-10 was shown to stimulate (not antagonize) Tim-1 on regulatory B cells, a newly identified population whose function in kidney injury is not clear.6.Ding Q. Yeung M. Camirand G. et al.Regulatory B cells are identified by expression of TIM-1 and can be induced through TIM-1 ligation to promote tolerance in mice.J Clin Invest. 2011; 121: 3645-3656Crossref PubMed Scopus (369) Google Scholar In addition, RMT1-10 has been reported to be an antagonist of Th1/Th17 activation and also induced Th2 cytokine expression,2.Rennert P.D. Novel roles for TIM-1 in immunity and infection.Immunol Lett. 2011; 141: 28-35Crossref PubMed Scopus (48) Google Scholar indicating that the mechanism by which RMT1-10 affects T-cell activation is not well defined. Conversely, 3B3 antibody stimulates Th1 activation, even though it binds to the same domain of Tim-1 as RMT1-10.2.Rennert P.D. Novel roles for TIM-1 in immunity and infection.Immunol Lett. 2011; 141: 28-35Crossref PubMed Scopus (48) Google Scholar Recently, with the use of Tim-1 knockout and transgenic mice, it was reported that RMT1-4 is the only commercially available Tim-1-specific monoclonal antibody (RMT1-10 was not mentioned).5.Wong S.H. Barlow J.L. Nabarro S. et al.Tim-1 is induced on germinal centre B cells through B-cell receptor signalling but is not essential for the germinal centre response.Immunology. 2010; 131: 77-88PubMed Google Scholar These studies suggest that the current model for the role of Tim-1 in T-cell activation may require revision, and the antibody approach requires better definition of the mechanism of action. Several recent findings have suggested that the widely held notion that Tim-1 is a Th2 regulator requires reconsideration.2.Rennert P.D. Novel roles for TIM-1 in immunity and infection.Immunol Lett. 2011; 141: 28-35Crossref PubMed Scopus (48) Google Scholar In studies using Kim-1/Tim-1 knockout mice, Tim-1 expression was very low (or nonexistent) in activated T cells or Th2 cells.2.Rennert P.D. Novel roles for TIM-1 in immunity and infection.Immunol Lett. 2011; 141: 28-35Crossref PubMed Scopus (48) Google Scholar,5.Wong S.H. Barlow J.L. Nabarro S. et al.Tim-1 is induced on germinal centre B cells through B-cell receptor signalling but is not essential for the germinal centre response.Immunology. 2010; 131: 77-88PubMed Google Scholar Additionally, the Tim-1 knockout study demonstrated that Tim-1 may weakly contribute to inflammatory lung injury but not to Th2-cell activation.2.Rennert P.D. Novel roles for TIM-1 in immunity and infection.Immunol Lett. 2011; 141: 28-35Crossref PubMed Scopus (48) Google Scholar,5.Wong S.H. Barlow J.L. Nabarro S. et al.Tim-1 is induced on germinal centre B cells through B-cell receptor signalling but is not essential for the germinal centre response.Immunology. 2010; 131: 77-88PubMed Google Scholar Transgenic expression of Tim-1 in T cells did not stimulate Th2 differentiation.2.Rennert P.D. Novel roles for TIM-1 in immunity and infection.Immunol Lett. 2011; 141: 28-35Crossref PubMed Scopus (48) Google Scholar,5.Wong S.H. Barlow J.L. Nabarro S. et al.Tim-1 is induced on germinal centre B cells through B-cell receptor signalling but is not essential for the germinal centre response.Immunology. 2010; 131: 77-88PubMed Google Scholar Rather, Tim-1 expression was proposed to be present in subsets of activated B cells, dendritic cells, and invariant natural killer T cells,2.Rennert P.D. Novel roles for TIM-1 in immunity and infection.Immunol Lett. 2011; 141: 28-35Crossref PubMed Scopus (48) Google Scholar, 3.Xiao S. Zhu B. Jin H. et al.Tim-1 stimulation of dendritic cells regulates the balance between effector and regulatory T cells.Eur J Immunol. 2011; 41: 1539-1549Crossref PubMed Scopus (42) Google Scholar, 5.Wong S.H. Barlow J.L. Nabarro S. et al.Tim-1 is induced on germinal centre B cells through B-cell receptor signalling but is not essential for the germinal centre response.Immunology. 2010; 131: 77-88PubMed Google Scholar each of which have been implicated in the pathophysiology of kidney injury (Figure 1).11.Li L. Okusa M.D. Macrophages, dendritic cells, and kidney ischemia-reperfusion injury.Semin Nephrol. 2010; 30: 268-277Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar The potential function of Tim-1 in renal dendritic cells has not been well characterized.3.Xiao S. Zhu B. Jin H. et al.Tim-1 stimulation of dendritic cells regulates the balance between effector and regulatory T cells.Eur J Immunol. 2011; 41: 1539-1549Crossref PubMed Scopus (42) Google Scholar To test the specificity of Tim-1 function in T cells, Rag-1–/– mice were used to evaluate T-cell function in cisplatin-induced and ischemia-induced kidney injury.9.Nozaki Y. Nikolic-Paterson D.J. Yagita H. et al.Tim-1 promotes cisplatin nephrotoxicity.Am J Physiol Renal Physiol. 2011; 301: F1098-F1104Crossref PubMed Scopus (41) Google Scholar,10.Rong S. Park J.K. Kirsch T. et al.The TIM-1:TIM-4 pathway enhances renal ischemia-reperfusion injury.J Am Soc Nephrol. 2011; 22: 484-495Crossref PubMed Scopus (39) Google Scholar However, these mice lack both T and B cells. Splenocytes (which contain both T and B cells) were used for the adoptive transfer in the ischemia study.10.Rong S. Park J.K. Kirsch T. et al.The TIM-1:TIM-4 pathway enhances renal ischemia-reperfusion injury.J Am Soc Nephrol. 2011; 22: 484-495Crossref PubMed Scopus (39) Google Scholar Therefore, cells other than T cells might be contributing to the observed effects in Rag-1–/– mice. Following kidney injury, numerous proximal tubules become KIM-1 positive, and copious amounts (nanogram levels) of soluble KIM-1 protein are shed into extracellular spaces, including the urine.1.Bonventre J.V. Yang L. Kidney injury molecule-1.Curr Opin Crit Care. 2010; 16: 556-561Crossref PubMed Scopus (85) Google Scholar, 4.Ichimura T. Asseldonk E.J. Humphreys B.D. et al.Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells.J Clin Invest. 2008; 118: 1657-1668Crossref PubMed Scopus (555) Google Scholar, 7.Nozaki Y. Nikolic-Paterson D.J. Snelgrove S.L. et al.Endogenous Tim-1 (Kim-1) promotes T-cell responses and cell-mediated injury in experimental crescentic glomerulonephritis.Kidney Int. 2012; 81: 844-855Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar In contrast, few T cells are present in the injured kidney,7.Nozaki Y. Nikolic-Paterson D.J. Snelgrove S.L. et al.Endogenous Tim-1 (Kim-1) promotes T-cell responses and cell-mediated injury in experimental crescentic glomerulonephritis.Kidney Int. 2012; 81: 844-855Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 9.Nozaki Y. Nikolic-Paterson D.J. Yagita H. et al.Tim-1 promotes cisplatin nephrotoxicity.Am J Physiol Renal Physiol. 2011; 301: F1098-F1104Crossref PubMed Scopus (41) Google Scholar, 10.Rong S. Park J.K. Kirsch T. et al.The TIM-1:TIM-4 pathway enhances renal ischemia-reperfusion injury.J Am Soc Nephrol. 2011; 22: 484-495Crossref PubMed Scopus (39) Google Scholar and a very small proportion of the activated T cells have been proposed to be Kim-1/Tim-1 positive.7.Nozaki Y. Nikolic-Paterson D.J. Snelgrove S.L. et al.Endogenous Tim-1 (Kim-1) promotes T-cell responses and cell-mediated injury in experimental crescentic glomerulonephritis.Kidney Int. 2012; 81: 844-855Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar For instance, in the report by Nozaki and colleagues,7.Nozaki Y. Nikolic-Paterson D.J. Snelgrove S.L. et al.Endogenous Tim-1 (Kim-1) promotes T-cell responses and cell-mediated injury in experimental crescentic glomerulonephritis.Kidney Int. 2012; 81: 844-855Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar Kim-1/Tim-1-positive T cells account for only 2% of all activated CD4+ cells, and very few interstitial CD4+ T cells (1.3 per high-power field) are found in the glomerulonephritis kidney model. Additionally, immunostaining of Kim-1 in rodent acute kidney injury showed an absence of interstitial Kim-1, suggesting that Kim-1/Tim-1 expression is predominantly restricted to the tubules.4.Ichimura T. Asseldonk E.J. Humphreys B.D. et al.Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells.J Clin Invest. 2008; 118: 1657-1668Crossref PubMed Scopus (555) Google Scholar Consequently, there is a dramatic imbalance between nominal Tim-1 expression on a minority of T cells and abundant kidney tubular Kim-1 expression. The abundant amount of tubule and soluble Kim-1/Tim-1 may potentially sequester administered anti-Kim-1/Tim-1 blocking antibodies, as evident in binding of the injected RMT1-10 antibody to the apical side of tubules in the glomerulonephritis model (Figure 1).7.Nozaki Y. Nikolic-Paterson D.J. Snelgrove S.L. et al.Endogenous Tim-1 (Kim-1) promotes T-cell responses and cell-mediated injury in experimental crescentic glomerulonephritis.Kidney Int. 2012; 81: 844-855Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar Thus, inhibitory antibodies may not be the most efficient means of manipulating Kim-1/Tim-1 function on immune cells in the setting of tubular injury, and T cells may not express very much Kim-1/Tim-1. Thus, there remain many caveats in interpreting data from studies using antibodies against Kim-1/Tim-1. Antibody blocking experiments will require a standardized antibody with well-characterized functional properties and high specificity to Kim-1/Tim-1. In addition, Kim-1/Tim-1 cell-type-specific knockout or transgenic mice, such as CD3-derived T cell- or B cell-specific transgenic mice and Kim-1/Tim-1 knockout mice,5.Wong S.H. Barlow J.L. Nabarro S. et al.Tim-1 is induced on germinal centre B cells through B-cell receptor signalling but is not essential for the germinal centre response.Immunology. 2010; 131: 77-88PubMed Google Scholar can be used to assess the role of Kim-1/Tim-1 in immune cells during kidney injury. Cells isolated from Tim-1 knockout or transgenic mice can also increase the specificity of adoptive transfer experiments. It is likely that Kim-1/Tim-1's phagocytosis/endocytosis function is crucial in tubular injury and repair. Therefore, phagocytosis-specific functional knockout (mutant) mice and/or Kim-1-specific conditional knockout or transgenic mice should be used to evaluate Kim-1's function in the proximal tubule and the immune system. Even though obstacles remain, studies such as those of Nozaki et al.7.Nozaki Y. Nikolic-Paterson D.J. Snelgrove S.L. et al.Endogenous Tim-1 (Kim-1) promotes T-cell responses and cell-mediated injury in experimental crescentic glomerulonephritis.Kidney Int. 2012; 81: 844-855Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar using reagents that interfere with or activate Kim-1/Tim-1 should give us important insights into disease mechanisms and potentially lead to specific Kim-1/Tim-1 targeted therapies in humans.