CD28 costimulation is required for the generation of naturally derived regulatory T cells (nTregs) in the thymus through lymphocyte-specific protein tyrosine kinase (Lck) signaling. However, it is not clear how CD28 costimulation regulates the generation of induced Tregs (iTregs) from naive CD4 T-cell precursors in the periphery. To address this question, we induced iTregs (CD25 ؉ Foxp3 ؉ ) from naive CD4 T cells (CD25 ؊ Foxp3 ؊ ) by T-cell receptor stimulation with additional transforming growth factor␤ (TGF␤) in vitro, and found that the generation of iTregs was inversely related to the level of CD28 costimulation independently of IL-2. Using a series of transgenic mice on a CD28-deficient background that bears wild-type or mutated CD28 in its cytosolic tail that is incapable of binding to Lck, phosphoinositide 3-kinase (PI3K), or IL-2-inducible T-cell kinase (Itk), we found that CD28-mediated Lck signaling plays an essential role in the suppression of iTreg generation under strong CD28 costimulation. Furthermore, we demonstrate that T cells with the CD28 receptor incapable of activating Lck were prone to iTreg induction in vivo, which contributed to their reduced ability to cause graft-versushost disease. These findings reveal a novel mechanistic insight into how CD28 costimulation negatively regulates the generation of iTregs, and provide a rationale for promoting T-cell immunity or tolerance by regulating Tregs through targeting CD28 signaling. (Blood. 2011; 117(11):3096-3103) IntroductionRegulatory T cells (Tregs) play an essential role in the maintenance of immunologic tolerance to prevent autoimmune disease. The development of Tregs in the thymus requires Foxp3, a member of the group of transcription factors characterized by their winged helix-forkhead DNA-binding domain. 1 Although it is widely accepted that natural Tregs (nTregs) develop in the thymus, compelling evidence indicates that Tregs with an identical phenotype can be induced in the periphery from CD4 ϩ non-Treg precursors under certain conditions. For example, all CD4 ϩ cells from RAG Ϫ/Ϫ T-cell receptor (TCR)-transgenic (Tg) mice are CD25 Ϫ , but a small proportion of these cells convert to a CD25 ϩ Treg phenotype after adoptive transfer into antigen-bearing mice or mice that have been administered a tolerizing dose of peptide antigen. 2,3 Furthermore, de novo generation of CD4 ϩ CD25 ϩ Tregs from CD4 ϩ CD25 Ϫ cells can also occur in thymectomized mice. 4 Such Tregs that are induced in the periphery are called induced Tregs (iTregs). Although our understanding of the microenvironment for iTreg development in vivo is still limited, it is clear that TCR stimulation, transforming growth factor␤ (TGF␤), and interleukin-2 (IL-2) are required for their development. [5][6][7][8] A crucial regulator of Tregs is the CD28 receptor, a dominant costimulatory molecule for T-cell activation. The first clue to the critical role of the CD28 family in nTreg function was the observation that prevention of CD28 ligation with CTLA4-Ig exacerbated autoimmune dis...

Objective Distal radius fractures in the older population significantly impair grip strength. The aim of the study was to investigate whether a hand strength focused exercise program during the period of immobilization for nonoperatively managed distal radius fractures in this population improved grip strength and quality of life. Design This is a single-center randomized controlled trial with concealed allocation, assessor blinding, and intention-to-treat analysis. Fifty-two patients older than 60 yrs who experienced distal radius fractures managed nonoperatively with cast immobilization. The intervention group (n = 26) received a home hand strength–focused exercise program from 2 and 6 wks after injury while immobilized in a full short arm cast. The control group (n = 26) performed finger range of motion exercises as per protocol. Primary outcome was grip strength ratio of injured arm compared with uninjured arm. Secondary outcome included functional scores of the 11-item shortened version of the Disabilities of the Arm, Shoulder and Hand. Outcomes were measured at 2, 6, and 12 wks after injury. Results The intervention group significantly improved grip strength ratio at both 6 and 12 wks (6 wks: 40% vs 25%, P = 0.0044, and 12 wks: 81% vs 51%, P = 0.0035). The intervention group improved the 11-item Disabilities of the Arm, Shoulder and Hand score at 12 wks; however, this was not statistically significant (25 vs 40, P = 0.066). Conclusions A hand strength–focused exercise program for elderly patients with distal radius fractures while immobilized significantly improved grip strength.

Background Little is known about how to best communicate with older adults about dietary behaviors and related factors in complex chronic disease care. Photo‐based communication could promote efficient information exchange and activate patients to effectively communicate their lived experiences. We conducted a pilot study to assess the feasibility and acceptability of a photo‐based patient‐clinician communication intervention to promote dietary discussions in geriatric primary care. Methods Older adult patients with 2+ concurrent chronic conditions received in‐person training on photo‐taking with a smartphone before taking photos in response to the prompt, “What aspects of your everyday life affect what you eat and how much you have to eat?” Patients then shared photos and their narratives with their primary care clinician during a clinic visit. Patients and clinicians completed separate audio‐recorded post‐visit interviews to assess perspectives on the intervention. Interview transcripts were analyzed using a thematic analysis approach. Results Fourteen patient‐clinician dyads completed the study. All except one patient‐clinician dyad (93%) completed the intervention as trained. 93% of patients and 86% of clinicians reported that they would “definitely” or “probably” be willing to engage in a future visit with photo‐sharing. Patients and clinicians shared similar perspectives on how sharing of photos during the visit enhanced communication and information exchange about dietary practices and other health‐related factors, influenced clinical recommendations made during the visits, and strengthened the patient‐clinician relationship. Conclusion Incorporation of a photo‐based patient‐clinician communication intervention to promote discussions regarding diet and other health‐related factors could be a patient‐centered strategy to help deliver comprehensive geriatric primary care.

3728 CD28 costimulation is required for the generation of naturally-derived regulatory T cells (nTregs) in the thymus through Lck-signaling. However, it is not clear how CD28 costimulation regulates the generation of induced Tregs (iTregs) from naïve CD4 T-cell precursors in the periphery. To address this question, we induced iTregs (CD25+Foxp3+) from naïve CD4 T cells (CD25−Foxp3−) by TCR-stimulation with additional TGFβ in vitro, and found that the generation of iTregs was inversely related to the level of CD28 costimulation independently of IL-2. By using a series of transgenic mice on CD28-deficient background that bears WT CD28 or mutated CD28 in its cytosolic tail incapable of binding to Lck, PI3K or Itk, we found that CD28-mediated Lck-signaling plays an essential role in the suppression of iTreg generation under strong CD28 costimulation. Furthermore, we demonstrate that T cells with the CD28 receptor incapable of activating Lck were prone to iTreg induction in vivo, which contributed to their reduced ability to cause graft-versus-host disease. These findings reveal a novel mechanistic insight into how CD28 costimulation negatively regulates the generation of iTregs, and provide the rationale for promoting T-cell immunity or tolerance by regulating Tregs through targeting CD28-signaling. Disclosures: No relevant conflicts of interest to declare.