Table 1. CD28 ^null CD4 T-cell associations with different clinical conditions.

Disease	Characteristics of CD4 +28 − T cells	Invasion of disease-specific tissue	Correlation to disease and therapies	Possible self-antigens (residues) sharing sequences with cytomegalovirus (CMV) peptides	References
Multiple sclerosis (MS)	Pro-inflammatory (interferon-gamma [IFN-γ], tumour necrosis factor-alpha [TNF-α], and interleukin-2 [IL-2]) IL-15 amplifies pathogenic properties in patients Fully potent regulatory T cells can suppress their pro-inflammatory features but not their expansion	Cerebrospinal fluid and brain lesions	Worse outcome in relapsing-remitting MS (RRMS) More frequent evoked potentials in RRMS Worse Expanded Disability Status Scale (EDSS) score	CMV major capsid protein UL86 (981–1003) and MOG (34–56) Myelin basic peptide (93–105) and human herpesvirus-6 U24 (1–13)	20, 29, 41, 42, 43– 47
Rheumatoid arthritis (RA)	Proliferation mediated by fractalkine- expressing synoviocytes Dependent on chronic exposure from TNF- α/IL-15, resulting in limited T-cell receptor (TCR) diversity Pro-inflammatory (IFN-γ and TNF-α) In synovium, expresses chemokine receptors (CX 3CR1) Activates natural killer cell receptors (CD11b, CD57, and NKG2D)	Synovial fluid of affected joints Lung infiltration of CD4 + in RA-associated pneumonitis	Preclinical atherosclerotic changes (endothelial dysfunction and carotid artery wall thickening) Disease severity positively correlates with amount of subset present Pre-disposition to extra-articular inflammatory lesions Infliximab reduces CD4 +CD28 − T cells	Human collagen Type II (associated with HLA- DRB1*0401 and HLA- DQA1*0301-DQB1*0302	32, 48, 49, 50, 51, 52– 58
Graves’ disease	Pro-inflammatory (IFN-γ) Mainly express CD45RO (activated/memory T cells)	Eye muscle tissue, orbital fat tissue, and thyroid tissue	Severity of Graves’ disease Severity of goitre Serum FT3 and TRAb levels positively correlate Increased intracellular IFN-γ secretion in patients with Graves opthalmopathy Increased anti-thyrotropin receptor antibodies		22, 59, 60
Systemic lupus erythematosus (SLE)	Pro-inflammatory (IFN-γ) Increased percentage of CD4 +NKG2D + T cells Expression is induced by SLE monocytes	Skin lesions	Inversely correlates with regulatory T cells Disease severity (using both Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K] and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI])	CMV J1S = VASRPL F P PRSPGPS and HRES1 = PRHRHPQDPRSPGPA CMV protein gB and the autoantigen U1 70k C terminal half of HCMVpp65 and anti-nuclear antibodies (BALB/C mice)	61– 66
Cardiovascular diseases	Expression of killer immunoglobulin-like receptors (KIRs) (that is, KIR2DS2) Destabilising fibrous caps of atherosclerotic plaques Release of perforin and granzyme B causes lysis of endothelial cells and vascular smooth muscle damage (without TCR stimulation)	Preferential invasion of unstable plaques	Severity of atherosclerosis and unstable angina (UA) Acute coronary events in patients with UA Reduced by statin therapy	hHSP60 153–163 with CMV UL122 and CMV US28	57, 67– 69